DNA to Disease: Examining phenotypic expression of DNA mutations

DNA to Disease Examining phenotypic expression of DNA mutations

Jenny Kravitz (Methuen HS) and Kari Roberts (Tufts) Overview These lessons are designed to reinforce genetics concepts that define DNA structure and function the process of transcription and translation into a protein product and ultimately the effect on an individualrsquos observed phenotype Activities are designed in a case study format to provide an opportunity for students to apply fundamental genetics concepts (transcription translation gene expression mutations) so that they can better understand how mutations may or may not lead to phenotypic changes Students will be asked to serve as ldquodoctorsrdquo putting the previously learned genetics concepts into a medical context to increase student interest and relate material to personal experiences (newspaper articles family history newborn screening) Misconceptions

Human disease results directly from alterationsmutations in DNA (Students fail to recognize the intermediate steps involving RNA and protein expression)

All mutations are deleterious ldquobreakingrdquo the protein to completely prevent normal function (Students fail to recognize that affected proteins may have partial function or may be absent entirely)

Massachusetts Learning Standards Addressed Standard 3 Genes allow for the storage and transmission of genetic information They are a set of instructions encoded in the nucleotide sequence of each organism Genes code for the specific sequences of amino acids that comprise the proteins that are characteristic of that organism

Strand 32 Describe the basic process of DNA replication and how it relates to the transmission and conservation of the genetic code Explain the basic processes of transcription and translation and how they result in the expression of genes Distinguish among the end products of replication transcription and translation Strand 33 Explain how mutations in the DNA sequence of a gene may or may not result in phenotypic change in an organism Explain how mutations in gametes may result in phenotypic changes in offspring

Major Science Concepts Addressed

DNA structure and function RNA structure and function Protein structure and function Transcription Translation Mutations Phenotypes and genotypes Gene expression

Learning Objectives 1 Students will be able to explain the processes of transcription and translation 2 Students will be able to read and understand given data (graphs tables gels genetic

sequences) 3 Students will be able to interpret and apply data to explain how DNA mutations affect

each step in the process of gene expression 4 Students will be able to interpret and apply data to predict phenotype 5 Students will be able to communicate ideas effectively though visual aids and oral

presentation Materials

Patient analysis worksheet (for group work as teams of ldquodoctorsrdquo) Overhead teacher example worksheet (for modeling with Sickle Cell) Student example worksheet (for modeling with Sickle Cell) Patient summary sheet (description and data for each disease) Codon reference chart (ldquothe wheelrdquo) Rounds Analysis Worksheet (to use during presentations) Genetics formal assessment (given as pre- andor post-test) Posterboard (or large white sheets of paper) and markers

Duration Five class periods (50 minutes each) Prior Knowledge

DNA structure and function RNA structure and function Protein structure and function Transcription Translation Mutations Phenotypes and genotypes Gene expression Reading and understanding data (graphs tables DNA sequences gels)

Description Day One Modeling with Sickle Cell Anemia Learning Cycle Engage The instructor leads the class through an example using sickle cell anemia The instructor should put the Patient Analysis Worksheet up on the overhead (or using a projector) and give each student his or her own blank copy Students should also be given the Patient Summary Sheet for sickle cell anemia Through class discussion the instructor and the students should complete the patient analysis together The instructor should elicit answers from the students and the class should discuss the rationale behind each correct answer This discussion is likely to identify the specific misconceptions and points of confusion for each individual class which the

instructor should address as they come up Through this modeling students should understand how to complete the subsequent group activity and what is expected of them Day Two Analysis of Patient Learning Cycle Explore Students should be placed into groups of 4 Each group is a team of ldquodoctorsrdquo and they will be analyzing various medical case studies all of which are single gene disorders with variable penetrance Each group should be given one Patient Analysis Worksheet and one Patient Summary Sheet (various diseases) Each group of doctors should receive a different patient Using the sickle cell model as a guide teams should then analyze their own specific patient and complete the Patient Analysis Worksheet Day Three Preparation for Rounds Learning Cycle Explain Each team of doctors will be responsible for giving an oral presentation on their patient during ldquoroundsrdquo (next class) Requirements include a poster and an oral description of the genetic disease affecting the patient Two students in the group should be responsible for putting together the poster which should include a clear title the names of all doctors on the team a list of typical symptoms a flow chart describing the effects of the mutation (DNA rarr mRNA rarr protein rarr phenotype) and all applicable images associated with their disease (x-rays photographs gels etc) The other two students in the group will be responsible for orally describing the disease (patient presentation genetic cause applicable treatmenttherapy options) The two students should take turns Therefore during this planning day those students should split of the material to be presented and prepare notecards to use while presenting Thus half of the team is responsible for the visual component of the presentation and half of the team is responsible for the oral component of the presentation Day Four Rounds (Presentations) Learning Cycle Elaborate Each team should present their case to the all the other doctors (approx 5 mins) Before each presentation listening doctors should each be given a copy of the Rounds Analysis Worksheet While other teams are presenting all other doctors are responsible for paying close attention to the details of the disease being described At the conclusion of the presentation a short question and answer period (approx 2-3 min) should give all listening doctors a chance to probe for further information clarify information presented or simply provide feedback Listening doctors should also receive a short amount of time to complete and submit Rounds Analysis Worksheets (approx 2-3 min) Total time for each case is therefore approximately 10 minutes Day Five Quiz (formal summative assessment) Learning Cycle Evaluate The final component of the activity is a quiz (taken individually) which should directly target each of the learning objectives If desired by the instructor a version of this quiz can be given as a pre-assessment to determine both the studentsrsquo starting point (identify potential misconceptions) and the success of the activity in reinforcing the applicable genetics concepts

Assessment Formative The instructor should formatively assess students throughout the entire process in order to address areas of confusion and guide group progress The instructor will model disease analysis with the class by completing the disease worksheet interactively through class discussion The instructor should clarify as student confusion or misconceptions arise and the instructor should communicate expectations for subsequent group work The instructor should also formatively assess students during group work by circulating and interacting with each group as they analyze their patient or prepare for ldquoroundsrdquo Summative Instructor should summatively assess groups upon completion of ldquoroundsrdquo (oral presentation) Groups should turn in their patient analysis worksheet to be graded (see rubric A) and instructor should evaluate oral presentation (ldquoroundsrdquo) for groupindividual grade (see rubric B) Also students will have a formal summative assessment (quiz) on underlying concepts (learning objectives) for individual assessment (see Genetics formal assessment) Possible Extensions

Discuss examples of diseases in which proteins are over- or underexpressed (not just a ldquobrokenrdquo protein) examples of diseases which involve environmental factors and examples of disease that display less than 100 penetrance

Explore emerging genetic technologies which may be used to treat or correct the diseases studied in the cases

Implementation Report (2009) The ldquoDNA to Diseaserdquo lesson was implemented in two Honors freshman biology classes April 13-17 2009 In total there were 36 students 23 male and 13 female The classes had already formally learned all the applicable genetics concepts (see Prior Knowledge above) In addition they had just completed a protein gel electrophoresis lab in which they diagnosed patients as affected unaffected or carriers in respect to sickle cell anemia This provided an excellent segue into Day One of this lesson in which the classroom teacher modeled completion of the patient analysis worksheet using sickle cell anemia Class discussion during this modeling was extremely engaging for students who revealed their misconceptions as well as their personal interests in medical genetics At the conclusion of Day One the students had a good idea of what was expected of them during Day Two For Day Two the patient analysis students self-selected teams of doctors (4 students per group) and were assigned their cases No two teams of doctors received the same genetic disorder Using the sickle cell anemia sheet from Day One as a guide the students were able to successfully complete the patient analysis sheet Both the classroom teacher (Jenny Kravitz) and the higher education partner (Kari Roberts) circulated the room to work with students to clarify information answer questions and keep them on task In general the students appreciated analyzing ldquorealrdquo medical information (ie radiography films) even though the material was challenging at times At the conclusion of Day Two the majority of doctor teams had completed their patient analysis sheets On Day Three the student groups completed their patient analyses and prepared their presentations for rounds (Day Four) Students were given a large white sheet of paper and markers as well as a guide for setting up their poster (see Poster Format Guide) Again both the classroom teacher and the higher education partner circulated the room to assist and monitor students At the end of Day Three most of the doctor teams had completed their posters (a few groups took them home to complete) Day Four was when each class did rounds in which each team of doctors took approximately five minutes to give an overview of their patient (using their poster which was taped to the wall as a guide) The other students filled out the Rounds Analysis Worksheet during the presentation and used it as a guide to direct questioning after the formal presentation For most groups a significant question and answer period entirely student driven occurred after their 5-minute formal presentation Very little clarification was offered by the classroom teacher and the higher education partner and for the most part the students were able to field questions successfully The Rounds Analysis Worksheet appeared to drive students to participate in a thorough and interactive question and answer period which required more critical thinking for students to compare and contrast the various diseases and disorders On Day Five the students finished up rounds presentations that were overflow from Day Four After all presentations the students were given the post-test (Genetics Formal Assessment) Rounds posters were kept up on the walls of the classroom until the end of the school year which prompted discussions about genetic disorders in a variety of classes that did not participate in this lesson implementation further extending the impact

Analysis of pre- and post-test data The formal summative assessment tool was a 20 question (multiple choice) quiz This quiz was administered prior to the implementation comparison between the pre- and post-test scores are used to assess the strengths and weaknesses of our implementation Questions were drawn from both textbook and MCAS examinations Table 1 outlines the question source and the genetics concepts that are addressed

Table 1

Question Source Concepts 1 textbook 5 2 textbook 6 3 textbook 1 8 4 textbook 4 5 MCAS 5 6 textbook 2 7 MCAS 3 6 8 8 textbook 5 9 textbook 1 7 8

10 MCAS 3 4 8 11 MCAS 3 6 8 12 MCAS 1 6 7 13 textbook 1 2 14 textbook 1 2 15 textbook 1 16 textbook 6 17 MCAS 4 8 18 textbook 4 1 2 19 MCAS 1 20 textbook 5

Concept Definition (MA Learning Standard)

1 DNA structure and function (Mass 31 32) 2 RNA structure and function (Mass 32) 3 Protein structure and function (Mass 12 32) 4 Transcription (Mass 32) 5 Translation (Mass 32) 6 Mutations (Mass 33) 7 Phenotypes and genotypes (Mass 33) 8 Gene expression (Mass 32 33)

MCAS Questions (Table 2) Seven of the questions that we used were taken from the MCAS examination These questions tend to be integrative across concepts (average 229 concepts per questions) and therefore require the students to adopt a more critical thinking approach The range of percent correct answers for these questions was 25 - 92 Following implementation there were improvements for all questions however certain questions (10 and 12) were answered incorrectly by the majority of students

Table 2

Question

Pre Test Post Test

Improvement Correct Percent Correct Percent 5 27 075 31 089 015 7 19 053 22 063 016

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Textbook Questions (Table 3) Thirteen of the assessment questions were drawn from textbook materials On average these questions focused on 154 concepts Following implementation student scores improved for all but three of the questions (6 8 and 15) Students had a particularly difficult time with questions 9 16 and 18 despite improvements on the post test these questions were answered correctly by less than 50 of students

Table 3

Question

Pre Test Post Test Improvement

Correct Percent Correct Percent 1 17 047 23 066 028 2 22 061 31 089 031 3 33 092 34 097 006 4 13 036 24 069 047 6 28 078 23 066 - 016 8 23 064 16 046 - 028 9 10 028 12 034 019

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Genetics Concepts In order to determine if there were areas of knowledge that were underserved by our project we compared the average correct response rates with the questions clustered into eight main areas The Massachusetts state guidelines addressed by these questions are defined in Table 1 At the completion of this project students had a good working knowledge of the structure and function of DNA and RNA as well as an understanding of translation there were many concepts that they struggled with

Students baseline knowledge of Protein structure and function (Mass 12 and 32) was poor with only 41 of the questions covering this material answered correctly at the Pre test The Post test demonstrated improvements for all of these questions with 61 of questions answered correctly Students baseline knowledge of Transcription (Mass 32) was poor with only 35 of the questions covering this material answered correctly at the Pre test The Post test demonstrated notable improvements for all of these questions however students clearly still struggled with the concept as only 54 of questions were answered correctly Students baseline knowledge of Mutations (Mass 33) was poor with only 43 of the questions covering this material answered correctly at the Pre test The Post test demonstrated improvements for all of these questions however students clearly still struggled with the concept as only 62 of questions were answered correctly Students baseline knowledge of Phenotypes and genotypes (Mass 33) was poor with only 32 of the questions covering this material answered correctly at the Pre test The Post test did not demonstrate improvement for all of these questions as only 39 of questions were answered correctly Students baseline knowledge of Gene expression (Mass 32 and 33) was poor with only 47 of the questions covering this material answered correctly at the Pre test After implementation students were able to answer 61 of the questions accurately Summary Overall the implementation was quite successful Students enjoyed the lesson and showed a genuine interest in medical genetics Importantly test data showed improvement after completing the lesson suggesting that more traditional educational methods were enhanced by utilization of a case-study approach which may have more successfully addressed student misconceptions The assessments demonstrate that students still struggle to connect changes in DNA genotype with phenotype In retrospect some of the disease materials may have been too dense with medical terminology thus students were not able to focus on the genetics concepts Future revisions of the materials will contain embedded definitions of medical terminology In addition the workflow during classroom sessions felt somewhat rushed We feel that a one day extension of this curriculum will enable a more careful examination of the genetic concepts within the context of specific disease states We believe that this approach increased student interest in the topic and offered them an alternative method of learning With appropriate modifications in emphasis and support materials we expect that future implementations will demonstrate even greater improvements in student knowledge and understanding of the way in which alterations at the level of DNA result in human disease Both the classroom teacher and the higher education partner are committed to using this lesson next school year with incorporation of the aforementioned modifications

Drs __________________________________________ Block _____ Date __________

DNA to Disease Patient Analysis Worksheet 1 What is the name of the disease that affects your patient 2 Examine the disease information sheet for your patient

A Who does this disease typically affect B What are the symptoms

C How common is it (prevalence)

D What gene is affected in your patient E What type of DNA mutation causes this disease F Can this disease be inherited If so how

3 How can this disorder be diagnosed 4 What treatmenttherapy options would be recommended for a patient with this disease

5 Examine the DNA sequences for your patient and an unaffected individual A Write them here

Affected - Unaffected - B What differences do you see in the DNA nucleotides 6 Transcribe the DNA (patient and unaffected) into mRNA

A Write them here Affected ndash Unaffected - B What differences do you see in the mRNA nucleotides 7 Translate the mRNA into a polypeptide (Use your codon chart)

A Write them here Affected ndash Unaffected - B What differences do you see in the amino acids 8 How do all of these differences affect proteins in your patientrsquos body

Dr _____________________________________ Block_____ Date________________

DNA to Disease Rounds Analysis Worksheet Presenting Doctors ___________________________ ________________________ ___________________________ ________________________ Name of Disease _________________________________________________________ 1 What are the major symptoms of this disease (Give at least 3) 2 What is the name of the gene or protein that is involved in this disease 3 Describe the mutation that causes this disease A How does it affect the DNA B How does it affect the RNA C How does it affect the protein D How does this lead to the symptoms seen in the patient 4 Explain one way in which this diseasemutation is similar to your patientrsquos disease 5 Explain one way in which this diseasemutation is different from your patientrsquos disease How would you rate the rounds presentation given by these doctors (Choose one)

Excellent Very Good Good So-So Poor

Rubric A DNA to Disease Analysis (Patient and Rounds)

Doctor ____________________________________________________________ Disease __________________________

E F P MXCELLENT AIR OOR ISSING SCORE Patient Analysis Worksheet (30 points) ndash Evaluation of patient analysis worksheet completed by this student for hisher patient Disease Overview (6 points)

6-5 points Accurate and complete description of symptoms prevalence and genetics

4-3 points Accuracy issues or some missing information

2-1 points Significant missing information

0 points No disease overview (s 1 amp 2A-F)

Diagnosis Methods (3 points)

3 points Accurate diagnosis info

2 points Accuracy issues

1 point Partial information

0 points No diagnosis methods (3)

TreatmentTherapy (3 points)

3 points Accurate and complete description of treatmenttherapy options

2 points Accuracy issues or some missing information

1 point Significant missing information

0 points No description of treatmenttherapy options (4)

DNA Mutation (3 points)

3 points Affectedunaffected DNA written out with analysis

2 points Minor errors or minor problems with analysis

1 point Missing information or major problems with analysis

0 points No DNA mutation info (5A-B)

RNA Mutation (3 points)

3 points Affectedunaffected RNA written out with analysis

0 points No RNA mutation info (6A-B)

Protein Changes (3 points)

3 points Affectedunaffected AA written out with analysis

0 points No protein change info (7A-B)

Protein Effect on Body (9 points)

9-7 points Clear and correct explanation of protein effects in body

6-4 points Partial clarity of explanation or accuracy issues

3-1 points Missing info or major problems with explanation

0 points No explanation of protein effect on body (8)

Rounds Analysis Worksheet (20 points) ndash Evaluation of rounds analysis worksheets completed by this student for all other presentations during rounds Disease Overview (3 points)

3 points Accurate disease information (symptoms geneprotein)

0 points No disease overview (s 1 amp 2)

Mutation Overview (6 points)

6-5 points Accurate mutation info (DNA RNA protein)

0 points No mutation overview (3A-B)

Mutation Effect on Body (3 points)

3 points Clear explanation of mutation effect on body

1 point Minimal explanation of mutation effect on body

0 points No explanation of mutation effect on body (3C)

Similarities to Own Patient (4 points)

4-3 points Thoughtful comparison including 2 good similarities

2 points 1 good similarity or 2 mediocre similarities stated

1 point 1 mediocre similarity stated

0 points No similarities stated (4)

Differences from Own Patient (4 points)

4-3 points Thoughtful comparison including 2 good differences

2 points 1 good difference or 2 mediocre differences stated

1 point 1 mediocre difference stated

0 points No differences stated (5)

Other Comments

TOTAL SCOREhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip________50 points

Rubric B DNA to Disease ldquoRoundsrdquo (Oral Presentation)

Team Members ____________________________________________________________ Disease __________________________

E G F P MXCELLENT OOD AIR OOR ISSING SCORE Visual Aid (5 points)

5 points Well organized easy to read includes all required information

4-3 points A few issues with organization or readability

2 points Organization issues or some missing information

0 points No poster

Presentation Skills (4 points)

4 points All members actively involved in presentation loud and clear voices

3 points Most members involved mostly loud and clear voices

2 points Only some members involved some soft or unclear voices

1 point Most members not involved mostly soft or unclear voices

0 points No presentation

Symptoms (8 points)

8-7 points All symptoms described and explained clearly

6-5 points Most symptoms described and explained clearly

4-3 points Symptoms described but not explained clearly

2-1 points Partial description of symptoms lacking explanation

0 points No description of symptoms

Prevalence (4 points)

4 points Clear explanation of prevalence including statistics

3 points Statement of prevalence including statistics

2 points Statement of prevalence missing statistics

1 point Minimal mention of prevalence no statistics

0 points No mention of prevalence or statistics

Treatmenttherapy (4 points)

4 points Clear explanation of treatmenttherapy options

3 points Treatmenttherapy options mostly exlpained

2 points Some explanation of treatmenttherapy options

1 point Stated (not explained) treatmenttherapy options

0 points No mention of treatment or therapy options

Genetic Cause (10 points)

10-9 points Clear and correct explanation of mutation effects on DNA mRNA and polypeptide

8-6 points Mostly clear and correct explanation

5-3 points Partial clarity of explanation or accuracy issues with genetic cause

2-1 points Statement of cause with no explanation or incorrect information

0 points No mention of genetic cause of disease

ProteinBody Effect (10 points)

10-9 points Clear and correct explanation of mutation effects on protein and the body

5-3 points Partial clarity of explanation or accuracy issues with effects

2-1 points Statement of effects with no explanation or incorrect information

0 points No mention of effects on protein or in the body

Peer Review (5 points)

5 points Peers able to understand and relate to their disease rated mostly excellent

4-3 points Peers mostly able to understand and relate rated mostly very good andor good

2 points Peers have some difficulty understanding and relating rated mostly so-so

1 point Peers have great difficulty understanding and relating rated mostly poor

0 points Peers unable to review and give feedback

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Multiple Choice Identify the letter of the choice that best completes the statement or answers the question

____ 1 What happens during the process of translation

a Messenger RNA is made from DNA b The cell uses information from messenger RNA to produce proteins c Transfer RNA is made from messenger RNA d Copies of DNA molecules are made

____ 2 A mutation that involves a single nucleotide is called a(an) a chromosomal mutation c point mutation b inversion d translocation

____ 3 Genes contain instructions for assembling a purines c proteins b nucleosomes d pyrimidines

____ 4 What is produced during transcription a RNA molecules c RNA polymerase b DNA molecules d proteins

____ 5 The diagram below represents part of a process that occurs in cells

Which process is represented a meiosis c replication b osmosis d translation

____ 6 Which type of RNA functions as a blueprint of the genetic code a rRNA c mRNA b tRNA d RNA polymerase

____ 7 In phenylketonuria (PKU) an enzyme that converts one amino acid into another does not work properly Which of the following is the most likely cause of this genetic condition a an error in the transcription of the gene for the enzyme b a mutation in the DNA sequence that codes for the enzyme c an excess of the amino acids necessary to produce the enzyme d a structural variation in the amino acid modified by the enzyme

Name________________________________________ Block_____ Date____________________

____ 8 How many codons are needed to specify three amino acids a 3 c 9 b 6 d 12

____ 9 Which of the following statements is false a Some genes code for enzymes b The instructions for making some proteins are not specified by genes c An organismrsquos inherited traits depend on proteins d An organismrsquos genes determine its inherited traits

____ 10 Individuals with one form of lactose intolerance do not produce the enzyme lactase because the gene coding for the production of lactase is shut off in their cells This means that which of the following processes does not occur for the gene a hydrogenation c replication b mutation d transcription

____ 11 The diagram below shows the final steps of a biochemical pathway used by the bacterium Serratia marcescens to produce a red pigment molecule Letters X Y and Z represent intermediate molecules produced in the pathway Four enzymes are also involved in the pathway as shown

A mutant strain of S marcescens produces molecules X and Y but does not produce the red pigment molecule or molecule Z Based on this result it can be concluded that there must be a mutation in the gene coding for which enzyme a enzyme 1 c enzyme 3 b enzyme 2 d enzyme 4

____ 12 Which of the following best describes the result of a mutation in an organismrsquos DNA a The mutation may produce a zygote b The mutation may cause a phenotypic change c The mutation causes damage when it occurs d The mutation creates entirely new organisms

____ 13 Unlike DNA RNA contains a adenine c phosphate groups b uracil d thymine

____ 14 Which of the following is a nucleotide found in DNA a ribose + phosphate group + thymine b ribose + phosphate group + uracil c deoxyribose + phosphate group + uracil d deoxyribose + phosphate group + cytosine

____ 15 DNA is copied during a process called a replication c transcription b translation d transformation

____ 16 Which of the following is NEVER a frameshift mutation a substitution c deletion b insertion d point mutation

Name________________________________________ Block_____ Date____________________

____ 17 The mold Aspergillus flavus grows on grain A flavus produces a toxin that binds to DNA in the bodies of animals that eat the grain The binding of the toxin to DNA blocks transcription so it directly interferes with the ability of an animal cell to do which of the following a transport glucose across the cell membrane into the cytoplasm b produce ATP using energy released from glucose and other nutrients c transfer proteins from the endoplasmic reticulum to Golgi complexes d send protein-building instructions from the nucleus to the cytoplasm and ribosomes

____ 18 During transcription an RNA molecule is formed a that is complementary to both strands of DNA b that is identical to part of a single strand of DNA c that is double-stranded d inside the nucleus

____ 19 Which of the following statements best describes a DNA molecule a It is a double helix c It is composed of amino acids b It contains the sugar ribose d It contains the nitrogenous base uracil

____ 20 During translation the type of amino acid that is added to the growing polypeptide depends on the a codon on the mRNA only b anticodon on the mRNA only c anticodon on the tRNA to which the amino acid is attached only d codon on the mRNA and the anticodon on the tRNA to which the amino acid is attached

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz Answer Section

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

5 ANS D 2008 Biology - High School Question 39 Multiple-Choice Reporting Category Genetics Standard Genetics - B 32

6 ANS C

7 ANS B 2007 Biology - High School Question 28 Multiple-Choice Reporting Category Genetics Standard Genetics - B 33

8 ANS A

9 ANS B

11 ANS C 2008 Biology - High School Question 17 Multiple-Choice Reporting Category Genetics Standard Genetics - B 33

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

19 ANS A 2008 Biology - High School Question 24 Multiple-Choice

Name________________________________________ Block_____ Date____________________

Reporting Category Genetics Standard Genetics - B 31

20 ANS D

Achondroplasia

Achondroplasia is a disorder of bone growth Although achondroplasia

literally means without cartilage formation the problem is not in forming

cartilage but in converting it to bone particularly in the long bones of the

arms and legs

All people with achondroplasia have short stature The average height of an

adult male with achondroplasia is 131 centimeters (4 feet 4 inches) and the

average height for adult females is 124 centimeters (4 feet 1 inch)

Characteristic features of achondroplasia include an average-size trunk

short arms and legs with particularly short upper arms and thighs limited

range of motion at the elbows and an enlarged head (macrocephaly) with a

prominent forehead Fingers are typically short and the ring finger and

middle finger may diverge giving the hand a three-pronged (trident)

appearance People with achondroplasia are generally of normal intelligence

Health problems commonly associated with achondroplasia include episodes

in which breathing slows or stops for short periods (apnea) obesity and

recurrent ear infections In adulthood individuals with the condition usually

develop a pronounced and permanent sway of the lower back (lordosis) and

bowed legs Older individuals often have back pain which can cause

difficulty with walking Life span is usually normal although compression of

the spinal cord andor upper airway obstruction increases the risk of death in

infancy

Achondroplasia is the most common type of inherited disproportionate short

stature (short-limbed dwarfism) The condition occurs in 1 in 15000 to

40000 newborns

Diagnosistesting Achondroplasia can be diagnosed by characteristic

clinical and radiographic findings in most affected individuals In individuals

who may be too young to diagnose with certainty or in individuals with

atypical findings molecular genetic testing can be used to detect a mutation

in the FGFR3 gene

Molecular genetics

Mutations in the Fibroblast growth factor receptor 3 (FGFR3) gene cause

achondroplasia

More than 99 of individuals with achondroplasia have one of two mutations

in FGFR3 In about 98 of individuals the mutation is a G380R substitution

resulting from a G-to-A point mutation at nucleotide 1138 of the FGFR3

gene About 1 of individuals have a G-to-C point mutation at nucleotide

The penetrance of the gene is 100 meaning that all individuals who have

a single copy of the altered FGFR3 have achondroplasia

Normal DNA

CCG TAG GAG TCG ATG CCC CAC CCG AAG AAG GAC

Mutant DNA

CCG TAG GAG TCG ATG TCC CAC CCG AAG AAG GAC

FGFR3 gene product

The FGFR3 gene provides instructions for making a protein called fibroblast

growth factor receptor 3 This protein is part of a family of fibroblast growth

factor receptors that share similar structures and functions These proteins

play a role in several important cellular processes including regulation of cell

growth and division determination of cell type formation of blood vessels

wound healing and embryo development

The FGFR3 protein spans the cell membrane so that one end of the protein

remains inside the cell and the other end projects from the outer surface of

the cell This positioning of the protein allows it to interact with specific

growth factors outside the cell and to receive signals that control growth and

development When these growth factors attach to the FGFR3 protein the

protein triggers a cascade of chemical reactions inside the cell that instruct

the cell to undergo certain changes such as maturing to take on specialized

functions

The FGFR3 gene provides instructions for making a protein that is involved

in the development and maintenance of bone and brain tissue This protein

limits the formation of bone from cartilage (a process called ossification)

particularly in the long bones

Normal gene product Proteins in the family of fibroblast growth factor

receptors (FGFRs) have a highly conserved structure The mature fibroblast

growth factor receptor 3 protein like all of the FGFRs is a membrane-

spanning tyrosine kinase receptor with an extracellular ligand-binding

domain consisting of three immunoglobulin subdomains a transmembrane

domain and a split intracellular tyrosine kinase domain

In people with achondroplasia the substitution of an arginine for a glycine

causes the protein to be overly active which interferes with skeletal

development and leads to the disturbances in bone growth seen with this

disorder

Abnormal gene product The G380R mutation has been shown to result in

constitutive activation of the FGF receptor Targeted disruption of the FGFR3

gene causes enhanced growth of long bones and vertebrae in mice

suggesting that fibroblast growth factor receptor 3 negatively regulates bone

growth Thus FGFR3 mutations in achondroplasia can be interpreted as

gain-of-function mutations that activate the fundamentally negative growth

control exerted by the FGFR3 pathway

Genetic counseling Achondroplasia is inherited in an autosomal dominant

manner which means one copy of the altered gene in each cell is sufficient to

cause the disorder About 80 percent of people with achondroplasia have

average-size parents these cases result from a new (de novo) mutation in

the FGFR3 gene Such parents have a low risk of having another child with

achondroplasia

De novo gene mutations are more common when the father is over the age

of 35 (advanced paternal age) Studies have demonstrated that de novo

gene mutations causing achondroplasia are exclusively inherited from the

father These mutations appear to result from de novo events during

spermatogenesis in the unaffected father

In the remaining cases people with achondroplasia have inherited an altered

FGFR3 gene from one or two affected parents If an individual with

achondroplasia has a reproductive partner with normal stature there is a

50 risk in each pregnancy of having a child with achondroplasia When

both parents have achondroplasia the risk to their offspring of having

normal stature is 25 of having achondroplasia 50 and of having

homozygous achondroplasia (a lethal condition) 25 Individuals who

inherit two altered copies of this gene typically have very severe problems

with bone growth and are usually stillborn or die shortly after birth from

respiratory failure Prenatal molecular genetic testing is available

Management Recommendations for management of children with

achondroplasia include monitoring of height weight and head

circumference measures to avoid obesity MRI or CT for evaluation of signs

of spinal cord compression adenotonsillectomy continuous positive airway

pressure (CPAP) by nasal mask and tracheostomy to correct obstructive

sleep apnea surgery to correct spinal stenosis and educational support in

socialization and school adjustment

References for mutation locations

Shiang et al Cell 1994 Bellus et al 1995 Rousseau et al 1996

Reference for normal gene product

Green et al 1996

Abnormal gene product

Colvin et al 1996 Deng et al Cell 1996

Inheritance from father

Wilkin et al 1998

Hand xray Achondroplasia

Hand xray normal

Cystic Fibrosis

ldquoSalty baby syndromerdquo

Cystic fibrosis (CF) affects epithelia of the respiratory tract exocrine

pancreas intestine male genital tract hepatobiliary system and exocrine

sweat glands resulting in complex multisystem disease The disorders most

common signs and symptoms include progressive damage to the respiratory

system and chronic digestive system problems

The epithelia or cells that line our internal organs normally produce mucus

Mucus is a slippery substance that lubricates and protects the linings of the

airways digestive system reproductive system and other organs and

tissues In people with cystic fibrosis the body produces mucus that is

abnormally thick and sticky As a result of this abnormal mucus affected

individuals have lower airway inflammation and chronic endobronchial

(airways of the lungs) infection Over time mucus buildup and infections

result in permanent lung damage including the formation of scar tissue

(fibrosis) and cysts in the lungs The result is to severe problems with

breathing and recurrent bacterial infections in the lungs These infections

cause chronic coughing wheezing and inflammation

Most people with cystic fibrosis also have digestive problems because thick

sticky mucus interferes with the function of the pancreas The pancreas is an

organ that produces insulin (a hormone that helps control blood sugar

levels) It also makes enzymes that help digest food In people with cystic

fibrosis mucus blocks the ducts of the pancreas preventing these enzymes

from reaching the intestines to aid digestion Problems with digestion can

lead to diarrhea malnutrition poor growth and weight loss Some babies

with cystic fibrosis have meconium ileus a blockage of the intestine that

occurs shortly after birth

Cystic fibrosis used to be considered a fatal disease of childhood With

improved treatments and better ways to manage the disease many people

with cystic fibrosis now live well into adulthood Adults with cystic fibrosis

experience medical problems affecting the respiratory digestive and

reproductive systems For example most men with cystic fibrosis are unable

to father children (infertile) because the tubes that carry sperm (the vas

deferens) are blocked by mucus and do not develop properly This condition

is known as congenital bilateral absence of the vas deferens (CBAVD)

Infertility is also possible though less common in women with cystic

fibrosis

Today the overall median survival is 365 years (95 confidence intervals

337-400 years) Males with CF tend to survive longer than females

Prevalence

CF is the most common life-limiting autosomal recessive disorder in the

Caucasian population The disease incidence is 1 in 2500 to 3500 live births

among Caucasians Approximately 30000 affected persons live in the US

Cystic fibrosis is less common in other ethnic groups affecting about 1 in

17000 African Americans and 1 in 31000 Asian Americans

Molecular genetics

Mutations in the Cystic fibrosis transmembrane conductance regulator

(CFTR) gene cause cystic fibrosis CFTR gene is 230 kb long and contains 27

coding exons It produces a 65-kb mRNA product and encodes a 1480-

amino acid integral membrane protein that functions as a regulated chloride

channel in epithelial cells

The CFTR gene provides instructions for making a channel that transports

negatively charged chloride ions into and out of cells The flow of chloride

ions helps control the movement of water in tissues which is necessary for

the production of thin freely flowing mucus

Mutations in the CFTR gene disrupt the function of the chloride channels

preventing them from regulating the flow of chloride ions and water across

cell membranes As a result cells that line the passageways of the lungs

pancreas and other organs produce mucus that is unusually thick and

sticky This mucus clogs the airways and glands causing the characteristic

signs and symptoms of cystic fibrosis

Pathologic allelic variants More than 1000 CFTR mutations are known to

be associated with CF almost all are point mutations or small (1-84 bp)

deletions The most common mutation is ΔF508 (Phe508del) or delta F508

which accounts for an estimated 30-80 (depending on the ethnic group)

of mutant alleles In the Caucasian population 1 in 22-28 people is

heterozygous for the ΔF508 allele

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

Delta F508 is a 3 basepair deletion in Exon 10 The result is a deletion of a

Phenylalanine residue from the CFTR protein The resultant segment of DNA

is smaller than the wildtype DNA and this difference can be detected by

electrophoresis The smaller DNA migrates faster through the agarose gel

This mutant protein which is only one amino acid short of the wild type

protein is retained in the endoplasmic reticulum and cannot reach the cell

surface where it normally resides

Cystic fibrosis (CF) Phenotypic features of CF include but are not limited

to the following

Respiratory Pulmonary disease remains the major cause of morbidity and

mortality in CF Affected individuals have lower airway inflammation and

chronic airway infection Failure of lung defenses leads to bacterial infection

of the lining of the airways Early manifestations are chronic cough

intermittent sputum production and exertional dyspnea As the lung disease

progresses as a result of chronic infection structural injury to the airways

occurs with resulting bronchiectasis End-stage lung disease is characterized

by extensive damage to the airways (cystsabscesses) and accompanying

scarring of lung adjacent to airways

Gastrointestinal 15-20 of newborns diagnosed with CF have a history

of meconium ileus at birth Individuals with CF also malabsorb fat in their

intestinal tracts leading to diarrhea poor growth and malnutrition and skin

rashes due to deficiencies of fat-soluble vitamins and zinc Acute or chronic

recurrent inflammation of the pancreas with pain fever nausea and

vomiting can be a presenting manifestation

Cystic fibrosis-related diabetes mellitus may present in adolescence It is

diagnosed in 7 of those age 11 to 17 years The prevalence increases in

adulthood

Liver scarring and failure can also be seen in CF Liver disease is second to

pulmonary disease as a cause of mortality in CF (17 of deaths)

Fertility More than 95 of males with CF are infertile as a result of

azoospermia caused by altered vas deferens which may be absent atrophic

or fibrotic Women with CF are fertile although a few females have

abnormal cervical mucus that may contribute to infertility

Diagnosistesting Most commonly the diagnosis of cystic fibrosis (CF) is

established in individuals with one or more characteristic phenotypic features

of CF plus evidence of an abnormality in cystic fibrosis transmembrane

conductance regulator (CFTR) function CFTR function can be assessed using

either a sweat chloride test or transepithelial nasal potential difference The

more common sweat chloride test measures the amount of chloride

produced by the skin in response to a chemical called pilocarpine In

individuals with CFTR mutations sweat chloride levels are abnormally high

(gt60 mEqL) because without a normally functioning CFTR they cannot

bring chloride into their cells

Genetic counseling CF is inherited in an autosomal recessive manner

Therefore siblings of an individual with cystic fibrosis have a 25 chance of

being affected a 50 chance of being asymptomatic carriers and a 25

chance of being unaffected and not carriers Molecular genetic testing for

disease-causing mutation(s) in the CFTR gene is used for carrier detection in

population screening programs Prenatal testing is available for pregnancies

at increased risk for CF if the disease-causing mutations in the family are

Parents of a proband with cystic fibrosis (CF)

bull The unaffected parents are obligate carriers (heterozygotes) and

have an alteration in one copy of the CFTR gene

o If the disease-causing CFTR alleles have been

identified in the proband it is most informative

to test parents by molecular genetic testing

bull Carriers are generally asymptomatic

bull On rare occasions a parent may be diagnosed as affected

subsequent to the diagnosis of the child

Newborn screening Newborn screening using immunoreactive trypsinogen

(IRT) assays performed on blood spots has been implemented in most of the

United States Trypsinogen is synthesized in the pancreas in CF its release

into the circulation appears to be enhanced by abnormal pancreatic duct

secretions Thus IRT levels are elevated in cystic fibrosis Newborns found

to have abnormal IRT results are evaluated through sweat testing andor

molecular genetic testing of CFTR

Treatment of Manifestations

Respiratory

bull Intervention to treat or prevent pulmonary complications may

include antibiotics bronchodilators anti-inflammatory agents

mucolytic agents and chest physiotherapy (postural drainage

with chest percussion)

bull Lung or heartlung transplantation is an option for selected

individuals with severe disease

bull Sinus symptoms may require antibiotics andor surgery to

correct

Gastrointestinal

bull Nutritional therapy may include special formulas for infants or

tuge feeding often via an indwelling gastric feeding catheter

bull Pancreatic insufficiency is treated with oral pancreatic enzyme

replacement with meals

Endocrine

bull Diabetes mellitus is treated with dietary restrictions andor

insulin

Physical activity exercise and conditioning A regular exercise

program is important to all individuals in maintaining overall health For

persons with CF regular exercise has the added benefits of maintaining

bone health and improving airway clearance Although exercise improves

clearance of airway secretions it should be used more as an adjunct rather

than as a replacement for the individuals prescribed airway clearance

regimen

References

CT Helbich Radiology 1999

Chest xray normal

Chest xray cystic fibrosis

Chest CT scan normal

Chest CT scan cystic fibrosis

Familial Adenomatous Polyposis (FAP)

Introduction

Familial adenomatous polyposis (FAP) is an inherited disorder characterized

by cancer of the large intestine (colon) and rectum Individuals with FAP

develop hundreds to thousands of precancerous colonic polyps beginning

on average at age 16 years (range 7-36 years) By age 35 years 95 of

individuals with FAP have polyps without colectomy (removal of the colon)

colon cancer is inevitable The average age of colon cancer diagnosis is 39

years Some people have a variant of the disorder called attenuated familial

adenomatous polyposis in which polyp growth is delayed The average age

of colorectal cancer onset for attenuated familial adenomatous polyposis is

55 years

In people with classic familial adenomatous polyposis the number of polyps

increases with age and hundreds to thousands of polyps can develop in the

colon Also of particular significance are noncancerous growths called

desmoid tumors These fibrous tumors usually occur in the tissue covering

the intestines and may be provoked by surgery to remove the colon

Desmoid tumors tend to recur after they are surgically removed In both

classic familial adenomatous polyposis and its attenuated variant benign

and malignant tumors are sometimes found in other places in the body

including the duodenum (a section of the small intestine) stomach bones

skin and other tissues People who have colon polyps as well as growths

outside the colon are sometimes described as having Gardner syndrome

A milder type of familial adenomatous polyposis called autosomal recessive

familial adenomatous polyposis has also been identified People with the

autosomal recessive type of this disorder have fewer polyps than those with

the classic type Fewer than 100 polyps typically develop rather than

hundreds or thousands The autosomal recessive type of this disorder is

caused by mutations in a different gene than the classic and attenuated

types of familial adenomatous polyposis

Prevalence

The reported incidence of familial adenomatous polyposis varies from 1 in

7000 to 1 in 22000 individuals FAP (and associated colon cancer

syndromes) historically accounted for about 05 of all colorectal cancers

this figure is declining as more at-risk family members undergo successful

treatment following early polyp detection and prophylactic colectomy

Diagnosistesting The diagnosis relies primarily on clinical findings

Familial adenomatous polyposis (FAP) is diagnosed clinically in an individual

with one of the following

bull One hundred or more colorectal adenomatous polyps

Note The diagnosis of FAP is generally considered in

individuals with polyposis occurring before age 40 years

bull Fewer than 100 adenomatous polyps and a relative with FAP

Note Individuals with 100 or more polyps occurring at

ldquoadvancedrdquo ages (35 to 40 years or older) may be found to

have attenuated FAP

bull A personal history of colorectal cancer before age 60 years and a

family history of multiple adenomatous polyps

Other features variably present in FAP

Adenomatous polyps of the small bowel are observed in 50-90 of

individuals with FAP The lifetime risk of small bowel malignancy is 4-12

the majority occurs in the duodenum

Extraintestinal manifestations

Osteomas are bony growths found most commonly on the skull and

mandible however they may occur in any bone of the body Osteomas do

not usually cause clinical problems and do not become malignant they may

appear in children prior to the development of colonic polyps

Dental abnormalities Unerupted teeth congenital absence of one or more

teeth and other dental abnormalities have been reported in approximately

17 of individuals with FAP compared to 1-2 of the general population

Benign skin lesions include epidermoid cysts and fibromas that may be

found on any part of the body including the face and are mainly of

cosmetic concern

Desmoid tumors develop in approximately 10 of children and adults with

FAP These poorly understood benign tumors are locally invasive but do not

metastasize Desmoid tumors form predominantly within the abdomen or in

the abdominal wall but may also occur extra-abdominally Desmoid tumors

may compress abdominal organs or complicate abdominal surgery About

5 of individuals with FAP experience morbidity andor mortality from

desmoid tumors

Cancer outside of the gastrointestinal tract Individuals with FAP have a

small but measurable increase in pancreatic liver thyroid and brain cancer

Molecular genetics

Mutations in the APC (adenomatous polyposis coli) gene cause both classic

and attenuated familial adenomatous polyposis APC is a tumor suppressor

gene that plays a role in cell signaling

Most cases of colon cancer are thought to develop slowly over a period of

several years usually arising within a benign polyp Every polyp has the

potential to develop into cancer therefore individuals with more polyps are

at a much higher risk for cancer Mutation in APC is thought to be an

important step in the initial formation of polyps Inactivation of the APC

gene located on chromosome 5 is thought to lead to increased cell

proliferation and contribute to the formation of colonic polyps Several

genetic alterations must occur during the conversion of normal colon cells

into cells capable of forming tumors In many cases mutation of the APC

gene is thought to be one of the first steps Although most people with

mutations in the APC gene will develop colorectal cancer the number of

polyps and the time frame in which they become malignant depend on the

location of the mutation in the gene

Normal allelic variants The gene is alternatively spliced in multiple coding

and noncoding regions the main transcript has 15 exons with 8532 base

pairs that code for 2843 amino acids and result in a 3118-kd protein Exon

15 is large and comprises over three-quarters of the coding region of the

Pathologic allelic variants Over 826 different mutations have been found

in families with an APC-associated polyposis condition Mutations almost

always cause a premature truncation of the APC protein usually through

single amino-acid substitutions or frameshifts While mutations have been

found scattered throughout the gene they are predominantly located in the

5 end of the gene The most common APC mutation is a 5 basepair deletion

at codon 1309 as depicted below

Normal DNA

TTT CTT TTC TAA CCT TGA TC

Mutant DNA

TTT CTA ACC TTG ATC

Interestingly the location of APC mutation is linked to the average age of

symptom onset codon 1309 age 20 years between codon 168 and 1580

(excluding 1309) age 30 years and all others age 52 years

Normal gene product The APC protein product is a tumor suppressor The

presence of normal APC protein appears to maintain normal apoptosis (cell

death) and may also decrease cell proliferation probably through its

regulation of b-catenin

Abnormal gene product Disease-causing mutations in the APC gene most

often result in truncated protein products When the APC gene is mutated

and abnormal protein is present high levels of free cytosolic b-catenin

result Free b-catenin migrates to the nucleus binds to a transcription factor

Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor) which leads to

increasing proliferation or decreasing apoptosis

Penetrance

In FAP the penetrance of colonic adenomatous polyposis and colon cancer is

virtually 100 in untreated individuals

Management

Surveillance

Recommended surveillance of individuals known to have FAP or an APC

disease-causing mutation and individuals at risk for FAP who have not

undergone molecular genetic testing or who are members of families in

which molecular genetic testing did not identify a disease-causing mutation

bull Sigmoidoscopy or colonoscopy every one to two years beginning

at age ten to 12 years

bull Colonoscopy once polyps are detected

bull Annual colonoscopy if colectomy is delayed more than a year

after polyps emerge In individuals age ten to 20 years in

whom adenomas are smaller than 60 mm and without villous

component delay in colectomy may be considered

bull Esophagogastroduodenoscopy (EGD) beginning by age 25 years

or prior to colectomy and repeated every one to three years

Treatment of manifestations Colectomy is advised when more than 20 or 30

adenomas or multiple adenomas with advanced histology have occurred

Endoscopic or surgical removal of duodenal adenomas is considered if polyps

exhibit villous change or severe dysplasia exceed one centimeter in

diameter or cause symptoms

Testing of relatives at risk Molecular genetic testing for early identification

of at-risk family members improves diagnostic certainty and reduces the

need for costly screening procedures in those at-risk family members who

have not inherited the disease-causing mutation

Clinically available molecular genetic testing of APC detects disease-causing

mutations in up to 90 of probands with typical FAP Molecular genetic

testing is most often used in the early diagnosis of at-risk family members

as well as in confirming the diagnosis of FAP or attenuated FAP in individuals

with equivocal findings (eg lt100 adenomatous polyps)

Pattern of InheritanceGenetic counseling

FAP is inherited in an autosomal dominant manner

Use of molecular genetic testing for early identification of at-risk family

members improves diagnostic certainty and reduces the need for costly

screening procedures in those at-risk family members who have not

inherited the disease-causing mutation Additionally individuals diagnosed

with APC-associated polyposis conditions as a result of having an affected

relative have a significantly greater life expectancy than those individuals

diagnosed on the basis of symptoms [Heiskanen et al 2000] As colon

screening for those at risk for classic FAP begins as early as age ten to12

years molecular genetic testing is generally offered to children at risk for

classic FAP by age ten years

Approximately 75-80 of individuals with FAP have an affected parent

The remaining 20-25 of individuals with an APC-associated polyposis

condition have the altered gene as the result of a de novo gene mutation

Offspring of an affected individual have a 50 risk of inheriting the altered

APC gene Prenatal testing and preimplantation genetic diagnosis are

possible if a disease-causing mutation is identified in an affected family

member

Normal Colon

Colon of an individual with FAP

Gross pathology specimen Colon from an individual with FAP

Hereditary hemochromatosis (HHC) ldquoBronze diabetesrdquo Introduction Hereditary hemochromatosis (HHC) is an inherited disorder that increases the amount of iron that the body absorbs from the gut Symptoms are caused by this excess iron being deposited in multiple organs of the body Most commonly excess iron in the liver causes cirrhosis which may develop into liver cancer Iron deposits in the pancreas can result in diabetes Similarly excess iron stores can cause cardiomyopathy (damage to the heart muscle) pigmentation of the skin and arthritis Without therapy males may develop symptoms between age 40 and 60 years and females after menopause

Iron is an essential nutrient found in many foods The greatest amount is found in red meat and iron-fortified breads and cereals In the body iron becomes part of hemoglobin a molecule in the blood that transports oxygen from the lungs to all body tissues Healthy people usually absorb about 10 percent of the iron contained in the food they eat which meets normal dietary requirements People with hemochromatosis absorb up to 30 percent of iron Over time they absorb and retain between five to 20 times more iron than the body needs Because the body has no natural way to rid itself of the excess iron it is stored in body tissues specifically the liver heart and pancreas HHC is caused by mutations in the HFE gene This gene is located on chromosome 6 and one mutation leads to the substitution of the 282nd amino acid Cysteine (C) becomes tyrosine (Y) therefore the mutation is called C282Y The switch of amino acids is thought to affect how the HFE protein interacts with the transferrin receptor (TFR1) which plays an important role in iron homeostasis A less common mutation H63D has also been identified in the HFE gene but will not be addressed here Prevalence

HHC is the most frequent autosomal recessive disorder among individuals of European descent The prevalence of individuals with two HFE mutant alleles (homozygote) is about 3-5 in 1000 or 1300 This means that 11 of Caucasians carry one mutant allele (heterozygote) HFE mutations are much less common in other ethnicracial groups Among African Americans the frequency of homozygotes for hemochromatosis is about 1 in 7000 with 23 of that population being heterozygotes Hispanics have homozygote and heterozygote frequencies of 0027 and 30 respectively Interestingly only a small proportion of people carrying HFE mutations suffer any symptoms This may be attributable to both environmental (diet and blood loss) and genetic factors Genetics HHC is inherited in an autosomal recessive manner Usually the genetic risk to the siblings of an affected individual (the proband) of having HHC would be 25 However the high carrier frequency for a mutant HFE allele in the general population of European origin (11 of the population or 19 persons) means that on occasion one parent has two abnormal HFE alleles usually in the absence of clinical findings In such instances the risk to each sibling of a proband of being homozygous for HFE is 50 Although prenatal testing would be technically feasible when both parents carry identified HFE mutations such requests would be highly unusual because HHC is an adult-onset treatable disease and the homozygous C282Y mutation has low clinical penetrance Diagnosis HHC should be suspected in any individual presenting with clinical signs of advanced iron overload including

bull Hepatomegaly (enlarged liver) bull Hepatic cirrhosis bull Liver cancer (hepatocellular carcinoma) bull Diabetes mellitus bull Heart failure bull Hypogonadism bull Arthritis bull Progressive increase in skin pigmentation (ldquobronzingrdquo)

The diagnosis of HHC in individuals with clinical symptoms consistent with HHC andor biochemical evidence of iron overload is typically based on the results of two blood screening tests

1 A transferrin-iron saturation greater than 45 2 Elevated serum ferritin concentration (gt 1000)

The confirmatory test is molecular genetic testing of the HFE gene

Liver biopsy is useful to confirm hepatic iron overload particularly in individuals with presumed hemochromatosis who lack the common HFE mutations associated with HHC but it is not diagnostic for HHC Magnetic resonance imaging (MRI) can estimate liver iron content by utilizing the paramagnetic properties of iron This method has been approved by the Food and Drug Association for the evaluation of individuals with iron overload Natural History Individuals with HFE-associated hereditary hemochromatosis (HHC) who express the phenotype clinically have inappropriately high intestinal absorption of iron from a normal diet resulting in excessive tissue storage of iron which may result in damage in a number of end-organs and potentially organ failure Although previous reports have suggested that males are ten times more likely than females to have symptoms of organ failure resulting from HHC recent studies show that among individuals with HHC women are half as likely as men to develop complications of end-stage organ failure Affected individuals may be identified because of signs and symptoms related to iron overload most frequently however they are identified before symptoms develop either through detection of abnormal iron-related studies or by evaluation as family members at risk for HHC Symptoms related to iron overload usually appear between age 40 and 60 years in males and after menopause in females Occasionally HHC manifests at an earlier age but hepatic fibrosis or cirrhosis is rare before age 40 years Often the first signs of clinically expressed HCC are an enlarged liver (hepatomegaly) arthritis involving the metacarpophalangeal joints (hand knuckles) a progressive increase in skin pigmentation resulting from deposits of melanin and iron diabetes mellitus resulting from pancreatic iron deposits and heart failure resulting from build up of iron in the heart muscle By the time cirrhosis or liver failure is recognized about 50 of individuals have diabetes mellitus and 15 have heart failure or irregular heart rhythms Hepatomegaly may or may not be present early in the disease however asymptomatic individuals can occasionally have hepatomegaly on physical examination With progression of the disease liver cirrhosis may develop and be complicated by cancer and end-stage liver disease Other common symptoms early in the disease are joint stiffness and pain Males may have impotence from pituitary dysfunction Abdominal pain weakness lethargy and weight loss are common but nonspecific findings When individuals with HHC are identified through iron studies or screening of at-risk family members most (75-90) do not have any symptoms Liver biopsy can be helpful to determine prognosis

bull Individuals diagnosed and treated prior to the

development of cirrhosis appear to have normal life expectancy

bull Those identified after the development of cirrhosis have a decreased life expectancy even with iron depletion therapy

bull Individuals with cirrhosis who are treated have a better outcome than those who are not however treatment does not eliminate the 10-30 risk for liver cancer even years after successful iron depletion

Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign With iron depletion dysfunction of some affected organs (liver and heart) can improve however endocrine abnormalities and arthritis improve in only 20 of those treated Alcohol consumption causes worsening of symptoms in HHC In addition cirrhosis is much more common among C282Y homozygotes who consume excessive amounts of alcohol Death in clinically affected individuals with HHC is usually caused by liver failure liver cancer heart failure or an irregular heart rhythm However many individuals who are HFE mutant homozygotes (identified through screening) studies survive to old age Treatment of Manifestations Presence of characteristic clinical endpoints Treatment by phlebotomy is clearly indicated when clinical symptoms of hemochromatosis are present Therapeutic phlebotomy

bull The usual therapy is removal of the excess iron by weekly phlebotomy (ie removal of a unit of blood) until the serum ferritin concentration is 50 ngmL or lower Twice-weekly phlebotomy may be occasionally useful to accelerate iron depletion

bull Weekly phlebotomy is carried out until the hematocrit is 75 of the baseline hematocrit

bull Maintenance therapy is aimed at maintaining serum ferritin concentration below 50 ngmL and transferrin-iron saturation below 50 On average men require removal of twice as many units of blood as women Subsequent phlebotomies can be carried out to prevent reaccumulation of iron about every three to four months for men and once or twice a year for women

Treatment of iron overload

bull Periodic phlebotomy is a simple inexpensive safe and effective treatment Each unit of blood (400-500 mL) with a hematocrit of 40 contains about 160-200 mg of iron Each mL of packed red blood cells contains 1 mg of iron

bull Iron chelation (administration of the chemical that binds iron directly) is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible However this is uncommon in individuals with HHC

Liver transplantation Liver transplantation is the only treatment for end-stage liver disease from decompensated cirrhosis However the post-transplant survival among untreated individuals with HHC is poor Absence of characteristic clinical endpoints Current data suggest that even though serum ferritin concentration may rise over time development of end-organ damage from iron storage is rare Consequently there is no general agreement that phlebotomy treatment is indicated in the presence of biochemically defined abnormalities (ie elevated transferrin-iron saturation and elevated serum ferritin concentration) in the absence of characteristic clinical endpoints (ie diabetes mellitus cirrhosis and liver carcinoma) More long-term studies are required Molecular genetics Pathologic allelic variants At least 28 distinct HFE mutations have been reported most being missense or nonsense mutations One missense mutation accounts for the vast majority of disease-causing alleles in the population Cys282Tyr (C282Y nucleotide 845GgtA) This missense mutation removes a highly conserved cysteine residue that normally forms an intermolecular disulfide bond with beta-2-microglobulin and thereby prevents the protein from being expressed on the cell surface Nucleotide sequence Normal DNA TCT ATA TGC ACG GTC CAC CTC C282Y Mutant DNA TCT ATA TGC ATG GTC CAC CTC Detection of C282Y mutation Using a restriction enzyme digestion of the DNA sequence the presence of the C282Y mutation introduces a breakpoint in the DNA The result is two

smaller pieces of DNA In the absence of a mutation a single large DNA band is found

Lanes 1 and 5 = negative controls Lanes 3 4 7 = normal HFE sequence Lane 2 = Heterozygous for C282Y Lanes 6 and 8 = Homozygous for C282Y RNA With the exception of a single nucleotide change the messenger RNA for HFE is identical with or without the C282Y mutation Protein Normal gene product The largest predicted primary translation product is 348 amino acids which gives rise to a mature protein of about 321 amino acids after cleavage of the signal sequence The normal protein is then transported to the cell surface where it binds with another protein Beta-2-microglobulin and reduces the iron uptake Abnormal gene product The C282Y mutation destroys a key cysteine residue that is required for disulfide bonding with beta-2-microglobulin As a

result the HFE protein does not mature properly and becomes trapped in the endoplasmic reticulum and Golgi apparatus leading to decreased cell-surface expression The mechanistic basis for the phenotypic effect of other HFE mutations is not clear at present

References

GeneReviews NIH (Initial Posting April 3 2000 Last Update December 4 2006) Online Mendelian Inheritance in Man Thompson and Thompson (eds) Genetics in Medicine 6th Edition WB Saunders Co (New York) 2001

Skin image Lim R Kid Intl 2008

Liver histology normal

Liver histology iron overload and cirrhosis in hemochromatosis

Osteogenesis Imperfecta

ldquoBrittle bone syndromerdquo

Introduction

Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly

affect the bones The term osteogenesis imperfecta means imperfect bone

formation People with this condition have bones that break easily often

from mild trauma or with no apparent cause Multiple fractures are common

and in severe cases can occur even before birth Milder cases may involve

only a few fractures over a persons lifetime

There are at least eight recognized forms of osteogenesis imperfecta

designated type I through type VIII The types can be distinguished by their

signs and symptoms although their characteristic features overlap Type I is

the mildest form of osteogenesis imperfecta and type II is the most severe

other types of this condition have signs and symptoms that fall somewhere

between these two extremes Increasingly genetic factors are used to define

the different forms of osteogenesis imperfecta

The milder forms of osteogenesis imperfecta including type I are

characterized by bone fractures during childhood and adolescence that often

result from minor trauma Fractures occur less frequently in adulthood

People with mild forms of the condition typically have a blue or grey tint to

the part of the eye that is usually white (the sclera) and may develop

hearing loss in adulthood Affected individuals are usually of normal or near

normal height

Other types of osteogenesis imperfecta are more severe characterized by

frequent bone fractures that may begin before birth and result from little or

no trauma Additional features of these conditions can include blue sclerae

short stature hearing loss respiratory problems and a disorder of tooth

development called dentinogenesis imperfecta The most severe forms of

osteogenesis imperfecta particularly type II can include an abnormally

small fragile rib cage and underdeveloped lungs Infants with these

abnormalities have life-threatening problems with breathing and often die

shortly after birth

Prevalence

Considering all types OI affects an estimated 6 to 7 per 100000 people

worldwide The two mildest forms OI type I and OI type IV account for

considerably more than half of all OI (prevalence of 4-5 per 100000) OI is

found in all racial and ethnic groups

Clinical Diagnosis

The clinical diagnosis of OI depends on the presence of a number of

features Features of OI

bull Fractures with minimal or no trauma in the absence of

other factors such as abuse or other known disorders of

bull Short stature or stature shorter than predicted based on

stature of unaffected family members often with bone

deformity

bull Blue sclerae

bull Dentinogenesis imperfecta (DI) brown-grey

discoloration of the teeth

bull Progressive post-pubertal hearing loss

bull Additional clinical features including ligamentous laxity

and other signs of connective tissue abnormality

bull Family history of OI usually consistent with autosomal

dominant inheritance

Radiographic features of OI The radiographic features of OI change with

age Fractures of varying ages and stages of healing are seen often of the

long bones but may also include ribs and skull In addition Osteopenia

(thin bones) detected by dual energy X-ray absorptiometry (DEXA) or

regular xrays

Natural history

The severity of OI ranges from perinatal lethality to individuals with severe

skeletal deformities mobility impairments and very short stature to nearly

asymptomatic individuals with a mild predisposition to fractures normal

stature and normal life span Before the molecular basis of OI was

understood OI was classified into four types based on clinical presentation

radiographic features family history and natural history

OI type I OI type I is characterized by blue sclerae and normal stature A

small proportion of infants with OI type I have femoral bowing at birth The

first fractures may occur at birth or with diapering More often the first

fractures occur when the infant begins to walk and more importantly to fall

Fractures generally occur at a rate of a few to several per year and then

decrease in frequency after puberty Fracture frequency often increases

again late in adulthood especially after age 50 Affected individuals may

have anywhere from a few fractures to more than 100 but the fractures

usually heal normally with no resulting deformity

Most affected individuals have normal or near normal stature but may be

short compared to other members of their families

Joint hypermobility may contribute to morbidity

Progressive hearing loss occurs in about 50 of adults with OI type I

beginning as a conductive hearing loss but becoming a sensorineural hearing

loss in time

Other types of OI

OI type II Abnormalities characteristic of OI type II are evident at birth

Weight and length are small for gestational age The sclerae are dark blue

and connective tissue is extremely fragile The skull is large for the body size

and soft to palpation Extremities are short and bowed Hips are usually

flexed and abducted in a frog-leg position Although some fetuses with OI

type II die in utero or are spontaneously aborted more typically infants die

in the immediate perinatal period More than 60 of affected infants die on

the first day 80 die within the first week survival beyond one year is

exceedingly rare

OI type III The diagnosis of OI type III is readily apparent at birth

Fractures in the newborn period simply with handling of the infant are

common In some affected infants the number and severity of rib fractures

leads to death from pulmonary failure in the first few weeks of life Infants

who survive this period generally fare well although most do not walk

without assistance and usually use a wheel chair or other assistance for

mobility because of severe bone fragility and marked bone deformity

Affected individuals have as many as 200 fractures and progressive

deformity even in the absence of fracture Growth is extremely slow and

adults with OI type III are among the shortest individuals known with some

having adult stature of less than one meter (three feet) Usually sclerae are

blue in infancy but lighten with age Hearing loss generally begins in the

teenage years

OI type IV OI type IV is characterized by mild short stature adult-onset

hearing loss and normal-to-grey sclerae This is the most variable form of

OI ranging in severity from moderately severe to so mild that it may be

difficult to make the diagnosis Stature is variable and may vary markedly

within the family Sclerae are typically light blue or gray at birth but quickly

lighten to near normal Hearing loss occurs in some

Pregnancy Fertility is normal in OI For most women who have OI

pregnancy is uncomplicated The exception is women with OI type III who

may need to deliver by cesarian section due to a small pelvis

Diagnosistesting The clinical diagnosis of OI is based on family history

a history of fractures characteristic physical findings including blue sclerae

and radiographic findings Radiographic findings include fractures of varying

ages and stages of healing and osteopenia (thin bones) Analysis of type 1

collagen synthesized in vitro by culturing dermal fibroblasts obtained from a

small skin biopsy shows the structure and quantity of the collagen Such

biochemical testing detects abnormalities in 98 of individuals with OI type

II about 90 with OI type I about 84 with OI type IV and about 84

with OI type III

Molecular genetics

Genes COL1A1 and COL1A2 are the two genes associated with OI types I

II III and IV They encode the two chains pro αlpha1 and pro αlpha2

respectively of type I procollagen

Normal gene product and function

Collagens are a family of proteins that strengthen and support many tissues

in the body including cartilage bone tendon skin and the white part of the

eye (the sclera) Type 1 collagen is the most abundant form of collagen in

the human body Type 1 collagen creates layers of fibrils in the extracellular

matrix of bone giving bone its tensile strength and forming a template for

the deposition of inorganic minerals The type I procollagen molecule is

formed from of two pro alpha1 and one pro alpha2 collagen chains that

combine to form a helical structure The 21 ratio of pro alpha1 pro alpha2

is critical for normal assembly of collagen protein

Type 1 collagen owes its ability to form fibrils to its very specific amino acid

sequence Both the alpha1 chain encoded by COL1A1 and the alpha2 chain

encoded by COL1A2 are built from 338 uninterrupted repeats of the amino

acid sequence Glycine-X-Y where X is often proline and Y is often

hydroxyproline In order to form a Type 1 collagen protein two alpha1 and

one alpha2 chains associate assuming a triple helix formation (the fibril)

Presence of a glycine in every third position is critical for triple helix

formation since only glycine the smallest of the amino acids fits into the

confined space in the center of the triple helix

Individual collagen molecules are cross-linked to one another within these

fibrils The formation of cross-links results in very strong type I collagen

fibrils which are found in the spaces around cells The figure below

demonstrates the formation of Type 1 collagen translation of mRNA

assembly and processing of the triple helix crosslinking

About 90 of individuals with OI types I II III and IV (but none with OI

types V VI and VII) have an identifiable mutation in either COL1A1 or

COL1A2 Mutations in the COL1A1 and COL1A2 genes are responsible for

more than 90 percent of all cases of osteogenesis imperfecta

Most of the mutations that cause osteogenesis imperfecta type I occur in the

COL1A1 gene The COL1A1 mutations that are responsible for osteogenesis

imperfecta type 1 reduce the production of pro-αlpha1 chains With fewer

pro-alpha1 chains available cells can make only half the normal amount of

type 1 collagen A shortage of this critical protein underlies the bone fragility

and other characteristic features of osteogenesis imperfecta type 1 These

genetic changes reduce the amount of type I collagen produced in the body

which causes bones to be brittle and to fracture easily

Sample mutation from patient with Type I OI

Normal DNA

CCA CTT GGG CCT GGG TGA CCG

Mutant DNA

CCA CTT GGG TCT GGG TCA CCG

Genetic counseling

Osteogenesis imperfecta types I-V are inherited in an autosomal dominant

manner For types I-IV the proportion of cases caused by a de novo

mutation in either COL1A1 or COL1A2 varies by the severity of disease

Approximately 60 of individuals with mild OI have de novo mutations

virtually 100 of individuals with lethal (type II) OI and a smaller proportion

of those with OI type II have a de novo mutation Each child of an individual

with a dominantly inherited form of OI has a 50 chance of inheriting the

mutation and of developing some manifestations of OI Prenatal testing in

at-risk pregnancies can be performed by analysis of collagen synthesized by

fetal cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks

gestation if an abnormality of collagen has been identified in cultured cells

from the proband Prenatal testing in high-risk pregnancies can be

performed by molecular genetic testing of COL1A1 and COL1A2 if the

mutation has been identified in an affected relative Prenatal ultrasound

examination performed in a center with experience in diagnosing OI and

done at the appropriate gestational age can be valuable in the prenatal

diagnosis of the lethal form and most severe forms of OI prior to 20 weeks

gestation fetuses affected with milder forms may be detected later in

pregnancy when fractures or deformities occur

Management focuses on supportive therapy to minimize fractures and

maximize function minimize disability foster independence and maintain

overall health [Marini amp Gerber 1997] Ideally OI is managed by a

multidisciplinary team including specialists in medical therapy of OI

orthopedics and rehabilitation medicine Supportive therapy is individualized

depending upon the severity the degree of impairment and the age of the

patient Considerable support is generally required by medical personnel to

help parents feel comfortable caring for infants with OI type II

Normal lower extremity radiographs

Lower extremity radiographs from an infant with OI

DNA to Disease - Overview

Patient Analysis Worksheet

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Genetics Formal Assessment

Achondroplasia

Cystic fibrosis

Familial adenomatous polyposis

Hemochromatosis

Learning Objectives 1 Students will be able to explain the processes of transcription and translation 2 Students will be able to read and understand given data (graphs tables gels genetic

sequences) 3 Students will be able to interpret and apply data to explain how DNA mutations affect

each step in the process of gene expression 4 Students will be able to interpret and apply data to predict phenotype 5 Students will be able to communicate ideas effectively though visual aids and oral

presentation Materials

Patient analysis worksheet (for group work as teams of ldquodoctorsrdquo) Overhead teacher example worksheet (for modeling with Sickle Cell) Student example worksheet (for modeling with Sickle Cell) Patient summary sheet (description and data for each disease) Codon reference chart (ldquothe wheelrdquo) Rounds Analysis Worksheet (to use during presentations) Genetics formal assessment (given as pre- andor post-test) Posterboard (or large white sheets of paper) and markers

Duration Five class periods (50 minutes each) Prior Knowledge

DNA structure and function RNA structure and function Protein structure and function Transcription Translation Mutations Phenotypes and genotypes Gene expression Reading and understanding data (graphs tables DNA sequences gels)

Description Day One Modeling with Sickle Cell Anemia Learning Cycle Engage The instructor leads the class through an example using sickle cell anemia The instructor should put the Patient Analysis Worksheet up on the overhead (or using a projector) and give each student his or her own blank copy Students should also be given the Patient Summary Sheet for sickle cell anemia Through class discussion the instructor and the students should complete the patient analysis together The instructor should elicit answers from the students and the class should discuss the rationale behind each correct answer This discussion is likely to identify the specific misconceptions and points of confusion for each individual class which the

Table 1

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Table 1

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Table 1

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Table 1

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Table 1

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Table 2

Question

Pre Test Post Test

10 9 025 17 049 049 11 13 036 25 071 049 12 13 036 15 043 016 17 17 047 19 054 013 19 33 092 35 1 008

Table 3

Question

13 35 097 35 100 003 14 26 072 29 083 013 15 33 092 28 080 - 013 16 11 031 16 046 033 18 12 033 15 043 022 20 19 053 21 060 012

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Drs __________________________________________ Block _____ Date __________

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Dr _____________________________________ Block_____ Date________________

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Doctor ____________________________________________________________ Disease __________________________

Other Comments

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

0 points No poster

Symptoms (8 points)

Other Comments

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Name________________________________________ Block_____ Date____________________

DNA to Disease Quiz

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Name________________________________________ Block_____ Date____________________

MULTIPLE CHOICE

1 ANS B

2 ANS C

3 ANS C

4 ANS A

6 ANS C

8 ANS A

9 ANS B

13 ANS B

14 ANS D

15 ANS A

16 ANS A

18 ANS D

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Name________________________________________ Block_____ Date____________________

20 ANS D

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Achondroplasia

arms and legs

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

infancy

40000 newborns

in the FGFR3 gene

Molecular genetics

achondroplasia

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Normal DNA

Mutant DNA

FGFR3 gene product

functions

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

disorder

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

achondroplasia

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Green et al 1996

Wilkin et al 1998

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Hand xray normal

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Cystic Fibrosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

fibrosis

Prevalence

Molecular genetics

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Normal DNA

TAG TAG AAA CCA CAA

Mutant DNA

TAG TAA CCA CCA

to the following

adulthood

Respiratory

correct

Gastrointestinal

Endocrine

insulin

regimen

References

Chest xray normal

Introduction

55 years

Prevalence

have attenuated FAP

cosmetic concern

desmoid tumors

Molecular genetics

Normal DNA

Mutant DNA

TTT CTA ACC TTG ATC

Penetrance

Management

Surveillance

member

Normal Colon

References

Introduction

normal height

shortly after birth

Prevalence

Clinical Diagnosis

deformity

bull Blue sclerae

regular xrays

Natural history

loss in time

Other types of OI

exceedingly rare

teenage years

with OI type III

Molecular genetics

Normal DNA

Mutant DNA

Genetic counseling

Rounds Worksheet

Rubric A - analysis

Rubric B - rounds

Poster Format Guide

Achondroplasia

Cystic fibrosis

Hemochromatosis

Documents

DNA to Disease: Examining phenotypic expression of DNA mutations