Human Genetics II

1. Q: What is a pedigree?

A: A diagram showing inheritance of a trait or disease across generations.

2. Q: What is a proband?

A: The first person identified with a disorder who prompts investigation of the family.

3. Q: What do pedigree symbols represent?

A: □ Male; ○ female; shaded = affected; diagonal line = deceased; arrow = proband.

4. Q: What do Roman and Arabic numerals represent in pedigrees?

A: Roman numerals = generations; Arabic numerals = individuals within each generation.

5. Q: What are the key features of autosomal recessive inheritance?

A: Both sexes affected equally; may skip generations; parents of affected individuals are often unaffected carriers.

6. Q: If both parents are carriers (Aa × Aa), what is the risk for each child?

A: 25% affected (aa), 50% carrier (Aa), 25% unaffected non-carrier (AA).

7. Q: What causes cystic fibrosis?

A: Pathogenic variants in CFTR; autosomal recessive inheritance.

8. Q: What causes sickle cell disease, and what is its inheritance?

A: A point mutation in HBB produces hemoglobin S (HbS); disease is typically autosomal recessive. HbA and HbS are codominantly expressed in carriers.

9. Q: Why can the sickle cell allele provide an evolutionary advantage?

A: Heterozygous carriers have some protection against severe Plasmodium falciparum malaria.

10. Q: What are the key features of autosomal dominant inheritance?

A: Both sexes affected equally; often appears in successive generations; an affected heterozygous parent has a 50% risk of passing it to each child.

11. Q: What causes Marfan syndrome?

A: An autosomal dominant FBN1 variant affecting connective tissue, especially skeletal, ocular, and cardiovascular systems.

12. Q: What do penetrance and variable expressivity mean?

A: Penetrance = proportion of people with a genotype who express its phenotype. Variable expressivity = differences in severity or features among affected individuals.

13. Q: What causes achondroplasia?

A: An activating FGFR3 variant impairs growth-plate cartilage development; autosomal dominant, often due to a new mutation.

14. Q: What is the recurrence risk when a parent has Marfan syndrome or achondroplasia?

A: If the parent is heterozygous, 50% per pregnancy. Two pathogenic FGFR3 copies in achondroplasia usually cause a lethal condition.

15. Q: What is a de novo mutation?

A: A new genetic variant that arises rather than being inherited from an affected parent.

16. Q: Why are X-linked recessive disorders more common in males?

A: Males have only one X chromosome, so one pathogenic variant can cause disease.

17. Q: What are the main X-linked recessive disorders, their genes, and symptoms?

A:

• Hemophilia A — F8: factor VIII deficiency, prolonged bleeding, easy bruising, joint bleeds.

• Duchenne muscular dystrophy — DMD: progressive muscle weakness and degeneration.

• Red-green color blindness — OPN1LW, OPN1MW: difficulty distinguishing red and green.

• G6PD deficiency — G6PD: hemolytic anemia, jaundice, fatigue.

• Hunter syndrome — IDS: developmental delay and organ enlargement.

• Fabry disease — GLA: pain, kidney disease, and heart disease.

18. Q: If a mother is a carrier of an X-linked recessive disorder and the father is unaffected, what are the risks?

A: Each son has a 50% risk of being affected; each daughter has a 50% risk of being a carrier.

19. Q: Can an affected father pass an X-linked disorder to his son?

A: No. Fathers pass their Y chromosome to sons and their X chromosome to daughters.

20. Q: What is hemophilia A, and how can mutation type affect severity?

A: An X-linked recessive F8 disorder causing factor VIII deficiency. Nonsense and frameshift variants often cause severe disease; missense variants may cause milder disease.

21. Q: What are the key features of X-linked dominant inheritance?

A: One pathogenic X-linked variant can cause disease in either sex; some disorders are more severe in males.

22. Q: What happens when a father has an X-linked dominant disorder?

A: All daughters inherit his affected X chromosome; none of his sons inherit it from him.

23. Q: What are important X-linked dominant disorders, their genes, and prevalence?

A:

• Rett syndrome — MECP2: approximately 1 in 10,000–15,000 live female births.

• Fragile X syndrome — FMR1: approximately 1 in 4,000 males and 1 in 8,000 females; technically an X-linked disorder caused by a CGG-repeat expansion.

• X-linked hypophosphatemia — PHEX: approximately 1 in 20,000 individuals.

• Incontinentia pigmenti — IKBKG: approximately 0.7 in 100,000 individuals.

• Alport syndrome — COL4A5 (X-linked form): affects the kidneys, hearing, and eyes. COL4A3 and COL4A4 variants can cause autosomal forms; the listed prevalence is approximately 1 in 50,000 newborns.

24. Q: Why can female carriers of X-linked disorders show mosaic patterns of symptoms?

A: Random X-chromosome inactivation creates cell populations expressing different X chromosomes.

25. Q: What is mosaicism, and how can it arise?

A: Two or more genetically distinct cell populations originating from one fertilized egg; caused by postzygotic mutations, nondisjunction, or anaphase lag.

26. Q: What is hypohidrotic ectodermal dysplasia (HED)?

A: A disorder affecting hair, sweat glands, and teeth. It can be X-linked recessive (EDA) or autosomal recessive/dominant (variants in genes such as EDAR, EDARADD, or WNT10A).

30. Q: If an autosomal recessive disease affects 1 in 1,000 people, how do you calculate carrier frequency?

A: \(q^2=0.001\); \(q\approx0.0316\); \(p\approx0.9684\). Carrier frequency \(2pq\approx0.061\), or about 6.1%.

27. Q: What is the Hardy–Weinberg equation?

A: \(p^2+2pq+q^2=1\), with \(p+q=1\).

28. Q: What do \(p\), \(q\), \(p^2\), \(2pq\), and \(q^2\) represent?

A: \(p\) = frequency of allele A; \(q\) = frequency of allele a; \(p^2\) = AA; \(2pq\) = Aa carriers; \(q^2\) = aa.

29. Q: What conditions are required for Hardy–Weinberg equilibrium?

A: A large population, random mating, and no mutation, natural selection, or migration (gene flow).