Human Genetics III

1. Q: What is codominance?

A: Both alleles are fully expressed in a heterozygote. Example: AB blood type expresses both A and B antigens.

2. Q: What is alpha-1 antitrypsin deficiency (AATD)?

A: An autosomal codominant disorder involving the SERPINA1 gene; deficient alpha-1 antitrypsin can cause lung disease and liver disease.

3. Q: What is pseudoautosomal inheritance?

A: Inheritance of genes in homologous regions of the X and Y chromosomes (PARs) that behave like autosomal genes and can show father-to-son transmission.

4. Q: What is an example of a pseudoautosomal gene, and what does it do?

A: SHOX in PAR1; variants can cause short stature and skeletal abnormalities.

5. Q: What does mitochondrial DNA encode?

A: 37 genes: 13 proteins involved in oxidative phosphorylation, 22 transfer RNAs, and 2 ribosomal RNAs.

6. Q: What is the inheritance pattern of mitochondrial DNA?

A: Maternal inheritance—typically, affected mothers can pass mitochondrial variants to children of either sex; affected fathers do not transmit mtDNA.

7. Q: What are homoplasmy and heteroplasmy?

A: Homoplasmy = all mitochondrial DNA copies are the same. Heteroplasmy = a mixture of normal and mutant mitochondrial DNA.

8. Q: What is replicative segregation?

A: Mitochondria are randomly distributed between daughter cells during cell division, causing different proportions of mutant mtDNA in different tissues.

9. Q: What do pleiotropy, reduced penetrance, and variable expressivity mean?

A: Pleiotropy = one gene affects multiple traits. Reduced penetrance = some people with a variant show no phenotype. Variable expressivity = symptoms differ in type or severity.

10. Q: What is a dynamic mutation?

A: An unstable DNA repeat expansion, commonly a trinucleotide repeat, that can increase across generations.

11. Q: What is anticipation?

A: A genetic disorder appears at an earlier age or with greater severity in successive generations, often due to repeat expansion.

12. Q: What causes Huntington disease, and how is it inherited?

A: CAG repeat expansion in HTT on chromosome 4p16.3; autosomal dominant. Symptoms include chorea, cognitive decline, and mood changes.

13. Q: What are the CAG repeat ranges for Huntington disease?

A: Normal: 26 or fewer; intermediate: 27–35; reduced penetrance: 36–39; full penetrance: 40 or more.

14. Q: What causes myotonic dystrophy type 1, and what are its features?

A: CTG repeat expansion in DMPK on chromosome 19q13.3; autosomal dominant. Features include progressive muscle weakness, myotonia, cataracts, and cardiac conduction defects.

15. Q: How does anticipation differ between Huntington disease and myotonic dystrophy type 1?

A: Huntington disease anticipation is often associated with paternal transmission; congenital myotonic dystrophy is commonly associated with maternal transmission.

16. Q: What causes Fragile X syndrome?

A: CGG repeat expansion in FMR1 on the X chromosome; a full mutation typically causes promoter hypermethylation and gene silencing.

17. Q: What are the CGG repeat ranges for Fragile X syndrome?

A: Normal: generally 5–44; intermediate: 45–54; premutation: 55–200; full mutation: over 200.

18. Q: What are the main clinical features of Fragile X syndrome?

A: Intellectual disability, autism-related features, language difficulties, long face, prominent ears, hyperflexible joints, and postpubertal macroorchidism in males.

19. Q: What is epigenetics?

A: Regulation of gene expression without changing the underlying DNA sequence. Mechanisms include DNA methylation, histone modifications, and noncoding RNAs.

20. Q: What is genomic imprinting?

A: Parent-of-origin-specific gene expression in which one parental allele is silenced through epigenetic marks.

21. Q: What are examples of imprinted genes and their expression patterns?

A: IGF2 is normally expressed from the paternal allele; H19 is normally expressed from the maternal allele.

22. Q: What is the main difference between a genetic mutation and an imprinting defect?

A: A mutation changes the DNA sequence; an imprinting defect alters parent-specific gene expression, often through abnormal methylation.

23. Q: What causes Beckwith-Wiedemann syndrome, and what are its features?

A: Abnormal imprinting or regulation of 11p15.5 growth-related genes, including IGF2 and CDKN1C. Features include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, and increased embryonal tumor risk.

24. Q: What causes Prader-Willi syndrome?

A: Loss of expression of normally active paternal genes in chromosome 15q11–q13, often due to paternal deletion or maternal uniparental disomy.

25. Q: What are the key features of Prader-Willi syndrome?

A: Neonatal hypotonia, feeding difficulties in infancy, later hyperphagia and obesity, short stature, small hands and feet, hypogonadism, and intellectual or developmental difficulties.

26. Q: What causes Angelman syndrome?

A: Loss of maternal UBE3A expression in the brain, often due to maternal deletion of 15q11–q13; it can also result from UBE3A variants or other imprinting mechanisms.

27. Q: What are the key features of Angelman syndrome?

A: Severe developmental delay, minimal speech, seizures, ataxia, sleep difficulties, microcephaly, and frequent smiling or laughter.

28. Q: How do Prader-Willi and Angelman syndromes differ genetically?

A: Paternal expression lost → Prader-Willi. Maternal UBE3A expression lost in the brain → Angelman. Both can involve chromosome 15q11–q13.

29. Q: What is uniparental disomy (UPD), and how can it cause imprinting disorders?

A: Both copies of a chromosome come from one parent. This can eliminate the normally expressed contribution from the other parent, causing disorders such as Prader-Willi or Angelman syndrome.

30. Q: Why does the parent transmitting a chromosome 15 variant matter for imprinting?

A: The same region can cause different outcomes depending on parental origin: loss of paternal gene expression can cause Prader-Willi syndrome, while loss of maternal UBE3A expression in the brain can cause Angelman syndrome.