بسم الله الرحمن الرحيم

MENDELIAN INHERITANCE DR. Nasser A. Elhawary Prof. of Medical Genetics Faculty of Medicine Umm Al-Qura University

Some Definitions Genetic locus: is a specific position or location on a chromosome. Locus usually refers to a specific gene. Alleles are alternative forms of a gene at a given locus. Homozygous: A subject in which both alleles on a locus are identical. Heterozygous: A subject in which both alleles on a locus are different. Compound heterozygote: A subject having 2 different mutant alleles on a given locus.

Genotype: A genetic constitution of an individual. Some Definitions… Double heterozygote: A subject having two different mutant alleles at two different loci. Genotype: A genetic constitution of an individual. Phenotype: is the observed result of the interaction of the genotype with the environmental factors.

Pattern of Inheritance of Disorders enable Genetic Counseling to family members. show how disorders pass to their children? taking a family history can help to diagnose the hereditary disease. e.g. Osteogenesis Imperfecta, DMD

Pedigree and Terminology

Pedigree and Terminology

Mendelian Inheritance Single genes represent >16,000 disorders (traits). Autosomal inheritance Sex-linked inheritance Multifactorial inheritance usually doesn’t obey Mendel inheritance. e.g. height, weight, … etc or diabetes, hypertension

Autosomal Dominant Inheritance Pathological phenotypes manifest in the heterozygote state (i.e. mutant/normal, M/N). So, one can trace AD disorder via pedigree e.g. familial hypercholesterolemia. Genetic risks to AD: 50% affected individuals to any family. Pleiotropy is a single gene that may influence multiple, seemingly unrelated phenotypic traits (e.g. TB). In TB, learning difficulties, epilepsy, a facial rash. Variable expressivity: The clinical features in AD disorders can show striking variations from person to person, even in the same family (e.g. polycystic kidney disease, PKD).

Autosomal Dominant Inheritance… Reduced penetrance: Some heterozygotes of AD give rise to unclear abnormal clinical criteria. It is produced from the result of modifying effects of other genes or interaction with environmental factors. Non-penetrance (skip a generation): A heterozygote having NO clinical features of the disease. New mutations: may happen with AD affected person with normal parents.e.g.Achondroplasia that may be diagnosed by the 50% chance. - New dominant mutations due to increased age of a father. - Non-paternity or non-maternity Co-dominance: 2 allelic traits expressed in heterozygous states (e.g. AB blood grouping). Homozygosity in AD traits: Each of the couples is a heterozygous to AD disease. So, the offspring has a severe phenotype or has an earlier age of onset (e.g. FHC, achondroplasia).

Autosomal Dominant Inheritance AD allele: Punnett’s square showing 50% chance of inheriting disease; A= dominant mutant, a= normal recessive alleles. AD pedigree is characterized by vertical transmission and is confirmed when father-to-son transmission occurs.

Achondroplasia… A short-limbed dwarfism, in which the parents usually have normal stature, representing a ‘new mutation’.

Autosomal Recessive Inheritance Recessive traits manifest only when the mutant allele is present in homozygosity, M/M Heterozygotes (carriers) show no clinical features for the disorder (i.e. healthy). All affected individuals are in sibship (i.e. brother, sister). Genetic risks to AR: 25%

Autosomal Recessive Inheritance… Consanguinity: The rarer AR disorder, the greater the frequency of consanguinity among the parents of affected individuals (e.g. Alkaptonuria, in which ≥¼ of the parents were first cousins). - So, rare AR disorder are more likely to meet up in the offspring of cousins than offspring of unrelated parents.

Autosomal Recessive Inheritance AR allele: Punnett’s square showing 25% chance of inheriting disease; a= recessive mutant allele, A= normal dominant allele

Autosomal Recessive Inheritance… Pseudo-dominance: happens when AR homozygote has offspring in 50% risk. Locus heterogeneity: A disorder inherited in the same manner can be due to mutations in more than one gene (sensori-neural hearing impairment/deafness. e.g., 1ry AR microcephaly have 6 distinct loci. Disorders with the same phenotype due to different genetic loci ‘genocopies’. Mutational heterogeneity (compound heterozygotes).

X-Linked Recessive Inheritance XL recessive: Punnett’s square showing 50% chance of affected male; 50% chance of carrier female. Xh= a mutation for an X-linked gene

Transmitted by female heterozygote (healthy) to affected males. X-Linked Recessive Inheritance… An XL recessive usually manifests only in males (is said to be hemizygous). Transmitted by female heterozygote (healthy) to affected males. XL-heterozygote → affected male → obligate carrier daughter None of his son will be affected (e.g. Hemophilia, Queen Victoria was a carrier, but Edward VII was healthy). Examples: DMD, G6PD, …

Variable expression in Heterozygous female X-Linked Recessive Inheritance… Variable expression in Heterozygous female e.g. XL-Ocular albinism (depigmentn. of iris and oculus fundus). - This is due to random process of X-inactivation in which active-X carries the mutant allele. Females affected with XLR: female heterozygote manifest clin. criteria. Explanations: - Skewed X-inactivation - Numerical X-chr abnormalities (Turner Syndrome) - X-autosome translocation

X-Linked Recessive Inheritance… X-Autosome Translocations

X-Linked Dominant Inheritance XL dominant: Punnett’s square showing 50% chance of affected male; 50% chance of carrier female.

XL-dominant manifests in heterozygous females (such as males). X-Linked Dominant Inheritance… XL-dominant manifests in heterozygous females (such as males). XL-D resemble AD bcuz both the daughters and sons of the affected female have 50% chance risk. Difference: in case of XD, the patient male transmits the disease to all daughters but not to the sons. In XL-D, increase of risk to females. e.g. Vitamin D-resistant rickets & Charcot-Marie-Tooth disease.

Y-Linked (Holandric) Inheritance Only males are affected. Y-linked traits to all of his sons but not to daughters. Deletion of gene(s) involved in spermato-genesis (Y-chr) leads to infertility - e.g. Azoospermia (absence of sperm in semen), or oligospermia (little amount of sperms).

- So, transfer from X- to Y- or vice versa. Y-Linked Inheritance… Partial sex-linkage: - During meiosis, pairing occurs betn. homo-logous distal parts of the Xp and Yp chromo-somes (psuedoautosomal region). - So, transfer from X- to Y- or vice versa. Sex influence: Autosomal traits are expressed more in one sex than in another. e.g. males affects frequently in Gout, Baldness (AD). - Hemochromatosis, AR, are much less in females than in males.

Multiple Alleles & Complex Traits Multiple alleles are monogenic or polygenic. ABO blood group has 4 alleles (A1, A2, B, O) An individual can possess only 2 of them. So, women has 2 alleles to transmit, but man has only 1 allele to transmit bcuz…

Mitochondrial Inheritance Each cell have a thousands of copies of mitDNA mitDNA is more found in cells that have high energy requirements (e.g. brain, muscles). mitDNA is exclusively inherited from mother through the oocyte. mitDNA has a higher rate of spontaneous mutation than nuclear DNA. Accumulation of mutations in mitDNA is responsible for some somatic effects seen with ageing.

Mitochondrial inheritance… Only transmitted through females, so-called maternal or matrilineal inheritance