Monogenic Inheritance Patterns PDF

Monogenic inheritance patterns Wooclap MEDGENOM1 before lecture MEDGENOM2 after lecture Monogenic inheritance patterns Mendelian inheritance Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant (rare) Y-linked (hypothetical) Nonmendelian inheritance Mitochondr...

Monogenic inheritance patterns Wooclap MEDGENOM1 before lecture MEDGENOM2 after lecture Monogenic inheritance patterns Mendelian inheritance Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant (rare) Y-linked (hypothetical) Nonmendelian inheritance Mitochondrial/maternal  Autosomal dominant inheritance Affected parent A a Healthy parent a Aa aa a Aa aa Risk of disease = 50% (Aa) Each affected person has an affected parent (vertical trasmission). Each child of an affected parent has a 50% risk of being affected. Not transmitted by unaffected individuals. Males and females are equally likely to be affected. Transmitted by either sex to offspring of either sex. Strachan and Read, HMG5, Garland Science Risk of recurrence Affected heterozygote x Affected heterozygote x healthy parent affected heterozygote Affected parent Affected parent Affected parent A a Healthy parent A a a Aa aa A AA Aa a Aa aa a Aa aa Risk of disease = 50% Risk of disease = 75% Homozygotes may express a more severe phenotype than heterozygotes e.g. achondroplasia Autosomal recessive inheritance Healthy carrier A a Healthy carrier A AA Aa a Aa aa Risk of disease = 25% (aa) Affected children born to unaffected parents. Parents of affected individuals are asymptomatic carriers (heterozygotes). Each child of a mating between carrier parents has a 25% risk of being affected. Affected individuals in a family are usually siblings (horizontal transmission). Males and females are equally likely to be affected. Risk of recurrence Healthy carrier x Affected parent x healthy carrier healthy non-carrier Healthy carrier Healthy non-carrier Affected parent A a A A Healthy carrier A AA Aa a Aa Aa a Aa aa a Aa Aa Risk of disease = 25% No risk of disease All progeny are carriers Carrier risk A priori A posteriori ? A a A a A AA Aa A AA Aa a Aa aa a Aa aa Carrier risk: 1/2 Carrier risk: 2/3  X-linked dominant inheritance Healthy mother Affected mother X X XA X Affected father Healthy father XA XAX XAX X XAX XX Y XY XY Y XAY XY Risk of disease: Risk of disease: Daughters: 100% Daughters: 50% Sons: 0% Sons: 50% Affected individuals have an affected parent (vertical trasmission). Affected males transmit the disease phenotype to all daughters and no sons. Both female and male offspring of affected females have a 50% risk of inheriting the phenotype. Females are more frequently affected that males Strachan and Read, HMG5, Garland Science  X-linked recessive inheritance Carrier mother Non-carrier mother X Xa X X Affected father Healthy father X XX XaX Xa XaX XaX Y XY XaY Y XY XY Risk of disease: Risk of disease: Daughters: 0% Daughters: 0% Sons: 50% Sons: 0% Predominantly affects males. Affected males born to unaffected parents; mother is asymptomatic obligate carrier and may have affected male relatives. Each son of a female carrier has a 50% chance of being affected; each daughter of a female carrier has a 50% chance of being a carrier. No male-to-male-transmission of disease phenotype; all daughters of an affected male are obligate carriers. Strachan and Read, HMG5, Garland Science Carrier risk for an X-linked recessive disorder 100% 100% 50%  Consanguinity increases the risk of inheriting a recessive condition Autosomal recessive X-linked recessive Disease manifests in a previous Affected females generation Apparent male-to-male transmission Strachan and Read, HMG5, Garland Science Hypothetical Y-linked inheritance Affects only males. Affected males always have an affected father (vertical trasmission). All sons of affected males are affected. Strachan and Read HMG5 fig 5.7 adapted from Wang et l 2004 J Med Genet 41: e80 Apparent Y-linked inheritance Pedigree of Chinese family in which deafness segregates as Y-linked character (DFNY1) in affected males, age of onset is 7-27 years; unaffected males in generation VII were too young at time of examinantion to manifest hearing loss affected female VII-11 is probably a phenocopy (person with phenotype normally caused by a certain genotype, but who does not have that genotype) causative gene probably not normally on Y chromosome; affected males had a Y chromosome structural abnormality in which a 160kb fragment of chromosome 1 (including known deafness gene DFNA49) was inserted into Y chromosome Strachan and Read HMG5 fig 5.7 adapted from Wang et l 2004 J Med Genet 41: e80 Mitochondrial/maternal inheritance Affects both sexes. Transmitted by affected mother (maternal inheritance) to all offspring (with frequent exceptions) Not transmitted by affected father to any of his offspring (with extremely rare exceptions) Reading Strachan and Read. Human Molecular Genetics, 5th edition 2018 Chapter 5 Patterns of inheritance Thompson and Thompson. Genetics in Medicine, 8th edition 2016 Chapter 7 Patterns of single-gene inheritance