Lectures 3-4 Mendelian Inheritance

8/3/2019 Lectures 3-4 Mendelian Inheritance

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Inheritance

Mendelian DisordersBy

Dr Heba Kassem

Ph.D. (U.K), M.D.


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Learning Objectives

1. Definitions used in practice of medical genetics2. Mode of inheritance: single gene and polygenicinheritance

3. Symbols of a pedigree (family tree)4. Construct a pedigree

5. Determine patterns of Mendelian inheritance6. Mention examples of Mendelian inherited

disorders.


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Important Terms inMedical Genetics

LOCUS: position occupied by a given gene on achromosome ALLELE: alternative forms of a gene at a given

locus GENOTYPE: the genetic constitution of an

individual, the particular genes at a given locus PHENOTYPE: the observed expression of a

particular gene or genes POLYMORPHISM: two or more alternative

genotypes, >1% in a certain population or not

associated with a diseased phenotype regardlessof the frequency. MUTATION: permanent heritable change in

DNA sequence (types)


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Pedigree Study

Why study the family tree (pedigree) Transmission of a trait in a family

Its frequency among relatives Determine the mode of inheritance


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Pedigree symbols


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Single Gene Disorders

Disorders caused from single mutantgene with potentially large effect

Mendelian/Non Mendelian OMIM more than 11,000 disorder

These disorders occur in 1-2% of the

general population


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Mendelian Inheritance

Caused by a particular genotype at one locus(Single Gene Trait)

Autosomal or Sex chromosome linked Dominance and Recessiveness (refers to

characters and not genes) DOMINANT TRAIT: expressed in a heterozygote RECESSIVE TRAIT: expressed only in homozygote CARRIER:Heterozygous individual carrying a mutant

allele. He/She is phenotypically normal but can

transmit the mutant allele to his/her offspring. HEMIZYGOUS: males have a single gene on eachlocus on the X and Y chromosome


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Autosomal Dominant Inheritance An affected person usually has at least one

affected parent Vertical Transmission Affects either sex Transmitted by either sex (Pedigree) Homozygotes are rare usually present with a

more severe phenotype. Regulatory proteins of complex metabolic

pathways or key structural proteins Genetic Risk: A child of an affected parent has

a 50% chance of being affected (Punnettssquare 1)
http://lecture%201.ppt/http://lecture%201.ppt/


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Genetic Risk in ADdisorder
http://lecture%201.ppt/


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Pedigree of AD


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Examples of AD disorders Nervous System: Neurofibromatosis


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AD diseases

Polycystic KidneyDisease

Familial AdenomatousPolyposis


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Familial Hypercholestrolemia


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Skeletal AD disorders


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Examples of AD

disorders Urinary: polycystic kidney GIT: familial adenomatous polyposis

Hematopoeitc: Hereditary sherocytosis Metabolic: familial hypercholestrolemia

Skeletal: Marfan Syd, and Achondroplasia


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Autosomal Recessive

Disorders Affected people are born to unaffectedparents

Parents are asymptomatic carriers

Increased consanguinity among parents Affect either sex (pedigree) Usually enzyme proteins are involved Genetic risk: after birth of an affected

child there is 1:4 risk of recurrence(Punnetts square 2)
http://lecture%201.ppt/http://lecture%201.ppt/


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Genetic Risk in AR

disorders


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Pedigree of AR


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Examples of AR DisordersMetabolicSubstrate

Intermediate 1

Intermediate 2

End-product

Enzyme 1

Enzyme 2

Enzyme 3

M1 M2

Albinism

GalactosaemiaPhenylketonuriaGlycogen storage diseaseWilsons DiseaseHemochromatosis


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Other Examples of AR

Disorders Cystic Fibrosis Hematopoeitic: sickle cell anaemia,

thalasaemias

Endocrine: Cong Adrenal Hyperplasia (Sexlimitation)

Skeletal: Ehlers Danlos Syd (somevariants)


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X-Chromosome

Inactivation

Lyon Hypothesis

One X chromosome is active in the

cells of the females due to dosagecompensation

Intra-uterine random inactivation

Females are actually mosaics


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Barr Body


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X-linked Recessive

Inheritance Affects mainly males Affected males are usually born to asymptomatic

carrier mothers and usually have affected malerelatives (Pedigree)

Females are affected if the father is affectedand the mother is a an asymptomatic carrier ordue to skewed X-inactivation

Genetic risk: Affected males never transmit thetrait to their sons but all his daughters are

obligate carriers who can then transmit the traitto 50% of their sons, thus showing a diagonaltransmission (Punnetts square 3,4)
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Genetic Risk in X-Linked

Recessive disorders


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Pedigree of X-Linked

Recessive


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Examples of X-Linked

Recessive Disorders Musculoskeletal: Duchenne MuscularDystrophy

Blood: hemophilia A and B, glucose6phosphate dehydrogenasedeficiency

Immune: Agammagolbulinemia

Nervous: Fragile X syndrome
http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/


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DMD


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Fragile X-Syndrome


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X-Linked dominant

inheritance Affects either sex, but more females areaffected than males in a family (pedigree)

Females are often mildly affected

The child of an affected female regardlessof sex has a 50% chance of being affected

All daughters but non of the sons of anaffected male will be affected

Example: Vit D resistant rickets
http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/http://lecture%201.ppt/


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Pedigree of X-Linked

dominant disorders


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Y-Linked inheritance Affects only males All affected males have an affected

father Genetic risk: transmitted to all sonsof the affected male

Example: hairy ears, azospermia(infertility)


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Unusual features in single

gene patterns of inheritance Pleitropy: two or more apparentlyunrelated effects from a single gene

disorder Tuberous Sclerosis


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Variable expressivity: variation in thephenotype among generations of the

same family


gene patterns of inheritance


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Anticipation: The genetic disorderpresent in a more severe phenotype insuccessive generations




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Reduced Penetrance:The individual may

carry the mutant genebut does not show thedisorder skipgeneration

E.g. Retinoblastom(less than 100%penetrance)

Unusual features in single gene

patterns of inheritance


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New Mutation:affected child with anAD disorder with

normal parents orfamily history

Mosaicism: presenceof more than one cellline within anindividual

Unusual features in single genepatterns of inheritance


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Locus/Genetic heterogeneity: A disorderinherited in the same mode can result

from mutations in more than one gene(at different loci) and shows the samephenotype (congenital hearing loss)


http://../Post%20graduate%20geneticshttp://../Post%20graduate%20genetics

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Lectures 3-4 Mendelian Inheritance