Genetic Disorder 2.2010

7/29/2019 Genetic Disorder 2.2010

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Pattern of Inheritance

Dr. dr. Loeki Enggar Fitri, M.Kes, SpParK


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Objective

Understand the meaning of, and be able to define: genotype

phenotype, homozygous, heterozygous, locus, allele haplotype

Know the standard pedigree symbols and how they are used.

Know the characteristics of the different Mendelian and non

Mendelian patterns of inheritance and be able to identify the

following patterns in pedigrees: autosomal dominant ,autosomal

recessive, X-linked dominant, X-linked recessive, mitochondrial.

Be able to define and recognize examples of: allelic

heterogeneity, incomplete penetrance, locus heterogeneity

germline mosaicism, variable expressivity.


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Genetic Information

Gene basic unit of geneticinformation. Genes determinethe inherited characters.

Genome the collection of

genetic information.

Chromosomes storage unitsofgenes.

DNA- is a nucleic acid thatcontains the genetic instructionsspecifying the biologicaldevelopment of all cellular formsof life


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The DNA double helix, with sugar-phosphate back bone and nitrogenous

bases (complementary base pairing)

GENE

The human is estimated to have 50.000-100.000 structural genes and

approximately 9600 single gene trait have been identified

Jorde et al, 1999


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Human Genome

Most human cellscontain 46 chromosomes:

2 sex chromosomes (X,Y):

XY in males.XX in females. 22 pairs of chromosomes

namedautosomes. One member of each pair is

derived from the individualsfather while other member is

derived from the mother. The members of each pair of

autosomes are said to be homologbecause their DNA is very similar.

by Maayan FishelsonChanges made by Anna Tzemach


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Chromosome Logical Structure

Locus location of a gene/markeron the chromosome.

Allelethe differing sequences orone variant form of a gene/markerat a particularlocus.

The combination of alleles oneach chromosome is termedhaplotype

Locus1

Possible Alleles: A1,A2

Locus2Possible Alleles: B1,B2,B3



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Genotype, phenotype, homozygousand heterozygous(Jorde et al, 1999, Thompson &Thampson, 2005)).

Genotype- the genetic constitution of the organism. Thealleles that are present at a given locus a referred to as theindividuals genotype.

If an individuals has the same alleles on both members of achromosome pairs, he or she is said to be a homozygote. Ifthe alleles differ in DNA sequences, the individual is aheterozygote.

Hemizygote - having only one copy of a gene.

If a locus has two or more alleles whose frequencies eachexceed 1% in a population, the locus is said to bepolymorphic/polymorphism.


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One Locus Inheritance

heterozygote homozygote

21A | A a | a

A | a 3 4 a | a

A | a 5 6 a | a

Male

Female



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Genotype & phenotype.

Phenotype. The expression of a genotype. Phenotype isthe physical description of the character in an individual

organism for example, hair color, weight, or the presence or

absence of a disease.

Most diseases / phenotypes result from the interaction

between genes and the environment Some phenotypes are primarily genetically determined,

example: Achondroplasi. Other phenotypes require genetic

and environmental factors, example mental retardation in

persons with Phenylketonuria.

Some phenotypes result primarily from the environment orchance, example lead poisoning


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Genotypes Phenotypes (example)

Eb- dominantallele.

Ew- recessiveallele.

genotypes

phenotypes



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Monogenic DisordersMendelian Inheritance / Uni-factorial

Single gene traits caused by mutation ingenes in the nuclear genome are oftencalled Mendelian because they occur on

average in fixed proportion among theoffspring of specific types of mating.

Autosomal Inheritance

DominantRecessive

Sex linked InheritanceX - linkedY - linked / holandric


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3

Normal male

Affected male

Stillbirth

Abortion

MaleDeceased

Marriage

Divorced

Normal female

Affectedfemale

Three unaffected female

Illegitimate offspring

Consanguineous marriage

No offspring


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Sex uncertain

Pregnant

Marriage with

three children

Arrow indicates the

proband

Prenatal diagnosis withtermination of an affectedfetus

Non-identicaltwins

Identical twins

Male, heterozygous for

autosomal recessive trait

Female, heterozygous forAutosomal or X-linkedrecessive trait


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MENDELS KEY CONTRIBUTION

SEGREGATION (Mendels 1st Law)

INDEPENDENT ASSORTMENT (Mendels 2nd Law)

DOMINANCE AND RECESSIVENES

GENETIC CONCEPTGREGOR MENDELS CONTRIBUTION


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Two members of a gene pair segregate from each other into

the gametes, so half the gametes carry one member of thepair and the other half carry the other member of the pair.

Mendels 1st Law (Segregation)

Y / y y / y

y/y

Y/y

y

Y

all yGamete

production

Gamete

production



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Mendels 2nd Law

Independent Assortment

Different gene pairs assort independentlyin gamete formation.

Gene pairs on SEPARATE CHROMOSOMESassort independently at meiosis.

This law is true only in some cases.


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Independent assortment


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Parent h(short allele/recessive)

h(short allele/

recessive)

H (tall allele/

dominant)

Hh(tall) Hh(tall)

H (tall allele/

dominant)

Hh(tall) Hh(tall)


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Parent H (tall allele/dominant)

h(short allele/

recessive)

H (tall allele/

dominant)

HH(tall) Hh(tall)

h (short

allele/recessive)

Hh(tall) hh(short)


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This reflects the fact that the Halelle is dominant while the h alleleis recessive

A dominant allele exerts its effectboth in the homozygote (HH) andheterozygote (Hh)

A recessive allele is detected only

when it occurs in homozygousform (hh)


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Dominant vs. Recessive

A dominantallele is

expressed even if it ispaired with a

recessive allele.

A recessiveallele isonly visible when

paired with another

recessive allele. by Maayan FishelsonChanges made by Anna Tzemach


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Autosomal Dominant Inheritance

Affected fathers ormotherstransmit the phenotype to both

sons and daughters.

Affected offspring 50%

probability if parent heterozygotefor mutation and normal allele (see picture), 75 % probability ifboth the parent heterozygote forthe mutation

Affected males and femalesappear in each generation of thepedigree.

Males & females are affected in aequal proportion



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Autosomal Dominant Inheritance

There is no skipping of generations. This leads tovertical transmission pattern, in which thedisease phenotype is usually seen in one

generation after another.


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Biochemical basis of Dominant traits

Biochemical defect remained enigmatic

The mechanism :

Genetic disorders are caused by mutations

Mutations permanent changes in genes (DNA)

Dominant allele mutation

A half normal level of gene product is insufficient

to maintain a normal phenotype


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Autosomal Dominant disorders

Condition Familial hypercholesterolaemia

Adult polycystic kidney disease

Neurofibromatosis type I

Myotonic dystrophy

Polyposis coli Dominant blindness

Dominant congenital deafness

Von Willebrand disease

Marfan syndrome Achondroplasia

Huntington disease

Polydactyly/Syndactyly

Osteogenesis imperfecta

Gene locus?

17

19

19

5q

4


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Huntingtons disease

Autosomal dominant disorders with incompletepenetrance.

Neurological (nervous system) disorder that causesprogressive degeneration of brain cells

Characterized by choreiform movement andprogressive dementia

The disease locus : short arm chromosome 4, themutational basis involve expansion of CAG triplerepeat sequence

Meiotic instability is greater in the male than in thefemale

Treatment none (patients die in 10 15 years aftersymptoms appear)


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Huntington disease


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Myotonic dystrophy

Autosomal dominant inheritance

Characterized by slowly progressive weaknessand myotonia

The disease locus : chromosome 19, themutational basis involves expansion of anunstable CTG triple repeat sequence

Meiotic expansion is greater in the female than in

the male


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Neurofibromatosis type I (NFI)

A common disorder of the nervous system , the eye

and the skin that occurs in 1 in 35000 birth.

Autosomal dominant inheritance with complete

penetrance and variable expression

The disease locus : chromosome 17 where it encodes

a protein known as neurofibromin. This normally act

as a tumor suppressor by inactivating the RAS-

mediated signal transduction of mitogenic signaling

Multiple benign fleshy tumors, neorofibromas

Multiple flat, irregular pigmented skin lesion known as

cafe au lait spot


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Osteogenesis imperfecta

1. Neonatal fractures typical

of osteogenesis

imperfecta, an autosomaldominant disease

caused by rare mutations

in the type I collagen

genes COL1A1 andCOL1A2.

2. Variable expression Dr John LoughlinInstitute of Musculoskeletal Sciences

[email protected]

http://www.ndos.ox.ac.uk/ogg/
mailto:[email protected]:[email protected]


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Reduced penetrance, variable

expression. Penetrance is an all-or-none phenomenon: one either has the

disease phenotype or does not. Reduced penetrance orincomplete penetrance is an individual who has the genotype for

a disease, may not exhibit the disease phenotype at all, eventhough he or she can transmit the disease gene to the nextgeneration. Ex: Retinoblastoma, Huntington diseases.

Variable expression refers to the extent of expression of the

disease phenomena. In variable expression, the penetrancemay be complete but the severity of the disease can verygreatly. Ex: Neurofibromatosis type I, osteogenesis imperfecta


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Autosomal recessive disorders

Only manifest when the mutant

allele is present in a double dose homozygosity

One fourth (25%). of the offspring

of two heterozygous carriers will be

affected with the disorder. Quasi

dominant inheritance with a

recurrence risk of 50% is seen

when an affected homozygotes

mates with a heterozygote

Consanguinity is present more

often in pedigrees

The parent can be clinically normal

Male and female are affected in

equal proportion

by Maayan Fishelson

Changes made by Anna Tzemach


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Autosomal recessive inheritance

Affected male, female

Unaffected male, female

Consanguineous mating

A B

Horizontal distribution


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Biochemical defect of recessive traits

Often involve enzymatic

Each cell in the body usually produced about

50%. When the enzyme level is reduced 50%,

as in heterozygotes for a functionless gene atthe locus, the residual 50% of enzymes

molecules can be made to functional twice as

fast as normal


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Autosomal Recessive disorders

Condition Haemochromatosis

Cystic fibrosis

Recessive mental retardation

Phenylketonuria

Spinal muscular dystrophy

Recessive blindness

Sickle-cell anemia

Tay-Sachs

Gene locus6p

7q

12q

5q

15


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Cystic Fibrosis

Autosomal recessive inheritance

Characterized by recurrent chest infection and mal-absorbtion

The disease locus : chromosome 7, where the gene(CFTR) encodes the cystic fibrosis trans-membranereceptor protein

This act as a chloride channel and controls the levelof intracellular sodium chloride, which in turninfluence the viscosity of mucous secretion

Thickened mucous in bronchial tubes (problemsbreathing) and pancreatic duct (problems digesting)

Treatment mucous in lungs manually loosened andother treatments have raised life expectancy to 35-40years old


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Fig. 02-08

Treatment

for CF


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Sickle cell anemia

Sickle cell anaemia,

an autosomalrecessive

disease caused by

mutation in the

b-globin gene

Dr John Loughlin

Institute of Musculoskeletal Sciences

[email protected]://www.ndos.ox.ac.uk/ogg/


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Phenylketonuria (PKU)

Affects nervous system development

Caused by missing enzyme that normallyallows metabolism of the amino acidphenylalanine

Causes abnormal breakdown product(phenylketone) in urine

Symptoms severe mental retardation, blackurine

PKU allele located on chromosome 12

prenatal DNA test can detect it (andelevated phenylalanine in blood)

If detect place newborn on diet low inphenylalanine until at least age

X li k d d i i h i


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X-linked dominant inheritanceThe genes are located on the x-chromosomes

Hemizygous mutant allele on

his/her single X chromosome Manifest in the heterozygous

female and male

Females are affected about twice

as often as males

Affected male transmits the

disorder to all of his daughter and

to none of his sons

Affected heterozygous females

married to unaffected males passthe condition to half their sons and

daughters (50% probability)

The syndromes less severe in

heterozygous affected females than

in hemizygous affected males

X li k d d i t i h it


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X-linked dominant inheritance

IV

III

II

I

Vertical distribution


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Fragile X syndrome

Fragile X syndrome is a genetic disorder passed from parentto offspring through DNA.

It is caused by mutation of the FMR1 gene (Fragile X mental

retardation 1) on the X chromosome.

This mutation is the result of a trinucleotide repeat disorder. A section of the FMR1 DNA usually repeats a sequence

known as CGG (cytosine, guanine & guanine) 30-55 times.

For someone with Fragile X syndrome, this section repeats

itself 200-800 times.

This causes the FMR1 gene not to produce the FMRP(Fragile X mental retardation protein).

X li k d i i h it


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X-linked recessive inheritance

The genes mutations on the x-chromosomes

Characteristics:

1. Only males are affected

hemizygous

2. Females carriers heterozygotes,

compensate for a mutant gene on

one X-chromosome.

3. Affected males transmits the

mutant gene to all daughter

(heterozygous carriers)

4. Genetic risk : carrier female with

a normal male, each son has a50% change of being affected.

Each daughter has a 50% change

of being a carrier

5. Horizontal distribution


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Females affected with Xlinked recessive

disorders

Homozygosity for X-linked recessive disorders

Her mother was carrier and her father wasaffected

Her father was affected and her mother wasnormal but a new mutation was occurred onthe X chromosome transmitted to thedaughter

Her mother was a carrier, her father wasnormal new mutation occurred on the X

chromosome he transmitted to her daughter


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Haemophilia A

X linked recessive inheritance

Is cause by a deficiency of factor VIII

The most common mutation is cause by

inversion which disrupts the factor VIIIgene at intron 22

Treatment with factor VIII replacementtherapy is very effective

Dr John Loughlin

Institute of Musculoskeletal Sciences

[email protected]

http://www.ndos.ox.ac.uk/ogg/


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Duchene muscular dystrophy

X linked recessive inheritance

The disease locus : chromosome Xp21

The gene product dystrophin links intracellularactin with extracellular laminin.

The commonest mutational mechanism is adeletion which disturbs the translation readingframe


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Ylinked Inheritance

Y-linkage refers to when a phenotypic trait is determined

by an allele (or gene) on the Y chromosome. It is alsoknown as holandric inheritance.

As only males have a Y chromosome, the genes aresimply passed from father to son,

Affected male transmits to all his sons but to none of hisdaughter

The Y-chromosome is small and does not contain many

genes, therefore few traits are Y-linked, and so Y-linkeddiseases are rare.


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Non Mendelian Inheritance

Anticipation

Mosaicism

Uniparental disomy

Genomic imprinting


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Anticipation

The onset of the disease occurs at an earlierage in the offspring than in the parents

Disease occurs with increasing severity in

subsequent generations A real biological phenomenon occurring as a

result of the expansion of unstable tripletrepeat sequences


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Mosaicism

An individual or in a particular tissue of thebody can consist of more than one cell type orline

Result of an error (non disjunction) occurringduring mitosis at any stage after conception.Ex : a zygote with an additional chromosome21 might lose the extra chromosome in mitoticdivisison and continue to develop as a46/47+21 mosaic.

Result from a mutation occurs during cellproliferation, in somatic cells or duringgametogenesis.


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Mosaicism

Depend on when the mutation occurred inembryological development, before or afterthe separation of germline cells from somaticcells, individual could theoretically :

Both Somatic & gonadal mosaicism

Somatic mosaicism (some tissue of the body)features of a single gene disorder being

less severe in an individual than usual orbeing confined to a particular part of the bodyin a segmental distribution (ex. NF1)

Germline mosaicism (restricted to the gametelineage only) the parents are phenotypicallynormal but in which more than one of theirchildren was affected .


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Uniparental disomy

Individuals who have been shown to haveinherited both homologues of a chromosomepair from only one of their parents

It is presumed that the conceptus wouldoriginally be trisomic with loss ofchromosome leading to the normal disomicstate

Could arise as a result of a gamete from oneparent which does not contain a particullarchromosome homologue / nullisomic


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Genomic imprinting

The genes on homologous chromosomeswere expressed equally but the differentclinical features can result depending on

whether a gene is inherited from the father orfrom the mother

It was thought to involve epigenetic processsuch as methylation and histon modification,

to get imprint monoallelic gene expressionwithout change genetic sequences.(functionally hemizigote)

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Genetic Disorder 2.2010