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Inheritance Mendelian Disorders

By Dr Heba Kassem Ph.D. (U.K), M.D.

Learning Objectives
1. 2. 3. 4. 5. 6. Definitions used in practice of medical genetics Mode of inheritance: single gene and polygenic inheritance Symbols of a pedigree (family tree) Construct a pedigree Determine patterns of Mendelian inheritance Mention examples of Mendelian inherited disorders.

Important Terms in Medical Genetics

LOCUS: position occupied by a given gene on a chromosome 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 regardless of the frequency. MUTATION: permanent heritable change in DNA sequence (types)

Pedigree Study
Why study the family tree (pedigree)
Transmission of a trait in a family Its frequency among relatives Determine the mode of inheritance

Pedigree symbols

Single Gene Disorders

Disorders caused from single mutant gene with potentially large effect Mendelian/Non Mendelian OMIM more than 11,000 disorder These disorders occur in 1-2% of the general population

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 each locus on the X and Y chromosome

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 (Punnetts square 1)

Genetic Risk in AD disorder

Pedigree of AD

Examples of AD disorders
Nervous System: Neurofibromatosis

AD diseases

Polycystic Kidney Disease

Familial Adenomatous Polyposis

Familial Hypercholestrolemia

Skeletal AD disorders

Examples of AD disorders
Urinary: polycystic kidney GIT: familial adenomatous polyposis Hematopoeitc: Hereditary sherocytosis Metabolic: familial hypercholestrolemia Skeletal: Marfan Syd, and Achondroplasia

Autosomal Recessive Disorders

Affected people are born to unaffected parents 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)

Genetic Risk in AR disorders

Pedigree of AR

Examples of AR Disorders Metabolic

Substrate Enzyme 1 Intermediate 1 Enzyme 2 Intermediate 2 Enzyme 3 End-product Albinism
M1 M2
Galactosaemia Phenylketonuria Glycogen storage disease Wilsons Disease Hemochromatosis

Other Examples of AR Disorders

Cystic Fibrosis Hematopoeitic: sickle cell anaemia, thalasaemias Endocrine: Cong Adrenal Hyperplasia (Sex limitation) Skeletal: Ehlers Danlos Syd (some variants)

X-Chromosome Inactivation
Lyon Hypothesis One X chromosome is active in the cells of the females due to dosage compensation Intra-uterine random inactivation Females are actually mosaics

Barr Body

Affects mainly males Affected males are usually born to asymptomatic carrier mothers and usually have affected male relatives (Pedigree) Females are affected if the father is affected and the mother is a an asymptomatic carrier or due to skewed X-inactivation Genetic risk: Affected males never transmit the trait to their sons but all his daughters are obligate carriers who can then transmit the trait to 50% of their sons, thus showing a diagonal transmission (Punnetts square 3,4)

X-linked Recessive Inheritance

Genetic Risk in X-Linked Recessive disorders

Pedigree of X-Linked Recessive

Examples of X-Linked Recessive Disorders

Musculoskeletal: Duchenne Muscular Dystrophy Blood: hemophilia A and B, glucose 6phosphate dehydrogenase deficiency Immune: Agammagolbulinemia Nervous: Fragile X syndrome


Fragile X-Syndrome

X-Linked dominant inheritance

Affects either sex, but more females are affected than males in a family (pedigree) Females are often mildly affected The child of an affected female regardless of sex has a 50% chance of being affected All daughters but non of the sons of an affected male will be affected Example: Vit D resistant rickets

Pedigree of X-Linked dominant disorders

Y-Linked inheritance
Affects only males All affected males have an affected father Genetic risk: transmitted to all sons of the affected male Example: hairy ears, azospermia (infertility)

Unusual features in single gene patterns of inheritance

Pleitropy: two or more apparently unrelated effects from a single gene disorder Tuberous Sclerosis

Unusual features in single gene patterns of inheritance

Variable expressivity: variation in the phenotype among generations of the same family

Unusual features in single gene patterns of inheritance

Anticipation: The genetic disorder present in a more severe phenotype in successive generations

Unusual features in single gene patterns of inheritance

Reduced Penetrance: The individual may carry the mutant gene but does not show the disorder skip generation E.g. Retinoblastom (less than 100% penetrance)

Unusual features in single gene patterns of inheritance

New Mutation: affected child with an AD disorder with normal parents or family history Mosaicism: presence of more than one cell line within an individual

Unusual features in single gene patterns of inheritance

Locus/Genetic heterogeneity: A disorder inherited in the same mode can result from mutations in more than one gene (at different loci) and shows the same phenotype (congenital hearing loss)