Lectures Clinical Genetics

Dr. Aneela Javed

The Clinical Genetics course aims to:

1. Provide a programme of advanced study for graduates that will

equip them for future careers in medical genetics and related

areas;

2. Foster intellectual skills necessary to develop a critical and

comprehensive understanding of the scientific principles,

informatics and ethical frameworks that underlie the theory and

practice of medical genetics;

3. Develop skills for the collection, analysis, interpretation and

understanding of scientific data

Course Contents:

1. The place of genetics in medicine

2. Mendel’s laws

3. Inheritance pattern principles and clinical examples

4. Chromosome structural abnormalities and clinical examples

5. Principles of multi-factorial disease

6. Allele frequency

7. Genetic linkage

8. Gene mapping

9. Mutagenesis and DNA repair

10.Mutations

11.The molecular biology of

cancer

12.Familial cancers

13.Immunogenetics

14.Genetic disorders of the

immune system

15.Biochemical genetics

16.Clinical applications of

genetics

16.Pedigree drawing

17. Risk assessment

18.Dysmorphology

19.Chromosome analysis

20.Biochemical diagnosis

21.Reproductive genetic

counseling

22.Prenatal sampling

23.Clinical application of linkage

24.DNA profiling

25.Management of genetic

disease

26. Avoidance and prevention of

disease

27. Ethical and social issues in

clinical genetics

Pedigree

Inheritance modes

1. Autosomal

2. X linked

a) Dominant

b) Recessive

3. Y linked

4. Mitochondrial

5. Mosaicism

6. Penetrance

Major chr abnormalities and

their clinical relevance

1. Numerical

2. Structural

Course Contents:

WHY AND HOW TO STUDY CHROMOSOMES

Techniques 1. Karyotyping2. Hybridization3. qPCR4. RNA testing5. Protein testing6. CHR painting

HOW DO GENES WORK

1. Gene structure2. Splicing 3. Translation 4. Beyond translation5. epigenetics

EPIGENETICS:

1. Dosage compensation2. Imprinting3. Imprinting disorders4. DNA methylation

MUTATION ANLYSIS:

1. Causes2. Effects of

mutation3. Mutation

detection4. Clinical

examples

Prenatal sampling1. Invasive and non invasive tech2. Qualifying risks3. Ethical issues

Multifactorial disorders•Population genetics

CASE STUDIES

Recommended Books:•New Clinical Genetics by Andrew Read, Dian Donnai, Scion Publishing Ltd, Bloxham, Oxford Shire, UK.•Clinical genetics: a short course by Golder Wilson, Volume 3, Wiley-Liss.•Genetics in Practice: A Clinical Approach for Healthcare Practitioners by Jo Haydon, Wiley-Blackwell.•Medical Genetics at a Glance, 2nd Edition by Dorian J. Pritchard, Bruce R. Korf, Wiley-Blackwell.•Essential Medical Genetics, Edition 6th Edition by Edward S. Tobias, Michael Connor, Malcolm Ferguson Smith, Wiley-Blackwell.

Clinical Genetics

• Interpretation and drawing pedigree

• Modes of inheritance:

1- Autosomal

2- Sex linked

3 -Mitochondrial Inheritance

4 -Mosaicism

• Penetrance and variable expression

Exercises

The study of inheritance of a pathologic condition as well as genetic factors influencing its occurrence.

A chart of an individual's ancestors used in clinical genetics to analyze Mendelian inheritance of certain traits/familial diseases.

PEDIGREE

TOOL KIT FOR PEDIGREE ANALYSIS

Pedigree interpretationHow to write possible genotypes

XXXY

X Y X X

Activity: Draw pedigree for following case

Your patient, Anna, is 35 years old. She has a brother, Brad, who is 32. Anna and Brad are the only children of Charles, who died at 61 from cancer, and Nancy, who is alive and well at 57 years old. Anna is married to Don, who is 36, and they have identical 6-year-old twin boys, James and John. Brad and Linda have a 5-year-old daughter, Sarah, and a 2-year-old son, Michael. Brad and Linda are recently divorced.

1-Autosomal dominant: (draw all three cases…father , mother or both

affected)

•A vertical pedigree pattern, with multiple generations affected

•Each affected person normally has one affected parent

•Each child of an affected person has a 1 in 2 chance of being affected

•Males and females are equally affected and equally likely to pass the

condition on (Huntington)

MODES OF INHERITANCE

Autosomal

2-Autosomal recessive (draw all three cases…father , mother or

both affected)

•A horizontal pedigree pattern, with one or more sibs affected; often only a

single affected case

•Parents and children of affected people are normally unaffected

•Each subsequent sib of an affected child has a 1 in 4 chance of being

affected, 2/4 carriers

•Males and females are equally affected

•Affected children are sometimes the product of consanguineous

marriages. In families with multiple consanguineous marriages, affected

individuals may be seen in several generations

MODES OF INHERITANCE

3-X-linked recessive ( father , mother or both affected)

•A ‘knight’s move pedigree pattern- affected boys may have affected

maternal uncles

•Parents and children of affected people are normally unaffected.

Never transmitted from father to son

•Affects mainly males; females can be carriers, and affected males in

a pedigree are linked through females, not through unaffected males

• Subsequent brothers of affected boys have a 1 in 2 risks of being

affected ; sisters are not affected but have 1 in 2 risk of being

carriers. (Muscular dystrophy)

MODES OF INHERITANCE

4- X-linked dominant

• Vague concept of heterozygosity in males n females, dominance

n recessiveness are not prominent for X linked. E.g X linked

hypophosphatemia

• Features very much similar to autosomal dominant pedigrees,

except that all daughters and no sons of an affected father are

affected

• Condition is often milder and more variable in females than in

males

RARE MODES OF INHERITANCE

5- Y-linked

•A vertical pedigree pattern

•All sons of an affected father are affected

•Affects only males, mostly leading to infertility

RARE MODES OF INHERITANCE

6-Mitochondrial

1- Matrilineal pattern of inheritance : passed

on by the mother, but never by father, affect

both sexes equally.

Leber hereditary optic neuropathy affects mostly males.

Leber’s hereditary optic

neuropathy (LHON) or Leber optic

atrophy is amitochondrially inherited

 (transmitted from mother to offspring)

degeneration of retinal ganglion cells

 (RGCs) and their axons that leads to an

acute or subacute loss of central vision;

this affects predominantly young adult

males. However, LHON is only

transmitted through the mother as it is

primarily due to mutationsin the

mitochondrial (not nuclear) genome and

only the egg contributesmitochondria to

the embryo.

ROS produced through the process of oxidative phosphorylation by the electron transport chain in mitochondria. NADH dehydrogenase mutations of complex I may increase the leaking of electrons from the chain, leading to increased accumulation of ROS, oxidative stress, and RGC death.

(2) Typical mendelian inheritance patterns

(3) HETEROPLASMY:

The proportion can vary between tissues and in the same

tissue over time low penetrance and extremely variable

expressivity.

(4) Ova contain many mitochondria: therefore a

heteroplasmic mother can have heteroplasmic children.

Fletcher case pattern.

RARE MODES OF INHERITANCE

Mitochondrial

When individual pedigrees are checked the initial hypothesis is based on two

questions:

1- does the pedigree show that the affected people have at least one affected parent.

If yes the condition is most likely dominant. If no is recessive.

2- are there any gender effects? Does the condition affects both sexes and can it be

passes on by parent of either sex to a child of either sex. If no gender effects

condition is most likely autosomal.

Male to male transfer is powerful pointer against X-linked inheritance as a father

should never transmitt his X t o son.

initial hypothesis / a quick decider

The proportion or % of individuals with the relevant mutation who exhibit clinical

symptoms.

Both syndrome and different features of same syndrome, can have different penetrance.

No-penetrance is pitfall in interpretation n counseling, a counselor should take care,

refer molecular testing.

PENETRANCE

Continuum of penetrance

• Spectrum of characters and genes from 100% to nill

•NEUROFIBROMATOSIS: mild to severe, 59exons so molecular

testing/mutational analysis is not effective in most cases.

A person whose body contains two or more genetically different cell lines is called a

mosaic.

Difficulty in genetic counseling.

For freshly arising mutations during mitosis and meiosis.

Mosaicsm can be important under following conditions:

(1) If the mutant cells have a tendency to grow and take over

(2) If the mutation arose sufficiently early in embryonic development , The person may

show features of milder disease phenotype or with a patchy distribution reflecting the

distribution of mutant cells

(3) Germ-line mosaicism (sperm or egg cells or their progenitors) is a major source of

uncertainty and confusion in pedigree interpretation and genetic counseling. Clinical

tests normal but children effected dominantly.

MOSAICISM

Assignment

1- Identify the mode of inheritance/ Any comments 2- Assign genotypes3- Risk of next child affected (arrowed person)