HUman Genetics IV

1. What is multifactorial inheritance?

👉 Interaction of multiple genes + environmental factors that contributes to a trait or disease.

2. How does multifactorial inheritance differ from Mendelian inheritance?

👉 Does not follow a simple single-gene dominant/recessive pattern; risk is probabilistic.

3. What are the principles of multifactorial inheritance?

👉 Increased family recurrence risk; closer relatives have higher risk; greater severity increases risk; sex bias may occur.

4. What is empirical risk?

👉 Recurrence risk estimated from observed family and population data rather than a simple Mendelian calculation.

5. What factors increase empirical recurrence risk?

👉 More affected relatives, closer genetic relationship, greater disease severity, and population-specific factors.

6. What is a quantitative trait? Give examples.

👉 A trait showing continuous variation, often influenced by many genes and the environment. Examples: height, blood pressure, BMI.

7. What is a qualitative trait? Give examples.

👉 A trait classified into distinct categories. Examples: ABO blood type and presence/absence of a particular congenital defect.

8. What is the threshold model?

👉 Genetic + environmental factors create a continuous liability; disease appears when liability exceeds a threshold.

9. What is the relationship between sex bias and recurrence risk?

👉 Relatives of the less commonly affected sex have higher risk if they develop the condition, because stronger genetic liability may be required.

10. What are neural tube defects (NTDs), and how can risk be reduced?

👉 Spina bifida and anencephaly; adequate maternal folic acid before conception and early in pregnancy reduces risk but does not eliminate it.

11. What is the recurrence risk pattern for NTDs after an affected child?

👉 Risk rises after one affected child and increases further after multiple affected children; lecture estimates are about 2–5% after one and 5–10% after two.

12. What is the key genetic pattern in pyloric stenosis?

👉 Multifactorial inheritance with male bias; relatives of affected females generally have higher recurrence risk than relatives of affected males.

13. What causes most cases of hypertension genetically?

👉 Polygenic susceptibility interacting with environmental factors, including diet, physical activity, stress, and socioeconomic influences.

14. How do type 1 and type 2 diabetes differ genetically and clinically?

👉 Type 1: autoimmune beta-cell destruction and little or no insulin production. Type 2: insulin resistance with progressive beta-cell dysfunction; family history and obesity are major risk factors.

15. What gene is strongly associated with type 2 diabetes susceptibility in the lecture?

👉 TCF7L2; variants contribute to susceptibility but do not determine disease by themselves.

16. What is a proto-oncogene?

👉 A normal gene that promotes or regulates cell growth, division, or signaling.

17. What is an oncogene, and how does it cause cancer?

👉 An activated proto-oncogene that promotes excessive cell proliferation, usually through a gain-of-function change.

18. What is a tumor suppressor gene?

👉 A gene that restrains cell division, repairs DNA, maintains genomic stability, or promotes apoptosis.

19. Compare oncogenes and tumor suppressor genes.

👉 Oncogene: excessive activity; usually one altered allele can have an effect. Tumor suppressor: loss of protective function; often both alleles must be inactivated.

20. What is Knudson’s two-hit hypothesis?

👉 Both alleles of a tumor suppressor gene must be inactivated for tumor development in the classic model.

21. What are the two hits in hereditary retinoblastoma?

👉 First hit: inherited or germline RB1 variant. Second hit: somatic inactivation of the remaining functional allele in a retinal cell.

22. How does hereditary retinoblastoma differ from sporadic retinoblastoma?

👉 Hereditary: first hit is present throughout the body, often causing earlier onset and bilateral/multiple tumors. Sporadic: both hits occur in a somatic retinal cell, more often producing unilateral disease.

23. What is the function of RB1?

👉 Tumor suppressor that restrains the cell cycle, particularly the transition from G1 to S phase

24. What is the function of TP53 (p53)?

👉 Responds to DNA damage by pausing the cell cycle, supporting DNA repair, or triggering apoptosis. Germline variants cause Li-Fraumeni syndrome.

25. What are BRCA1 and BRCA2, and what happens when they are mutated?

👉 Tumor suppressor genes involved in DNA double-strand break repair by homologous recombination; inherited pathogenic variants increase breast, ovarian, and certain other cancer risks.

26. What is the difference between inherited and sporadic cancer?

👉 Inherited cancer susceptibility begins with a germline pathogenic variant; sporadic cancer develops through acquired changes in somatic cells. Most cancers are sporadic.

27. How does a RAS mutation contribute to cancer?

👉 RAS is a small GTPase involved in growth signaling. Activating mutations can keep signaling abnormally active, promoting cell proliferation.

28. What is the Philadelphia chromosome?

👉 Translocation between chromosomes 9 and 22 creates the BCR-ABL1 fusion gene, producing an overactive tyrosine kinase associated especially with chronic myeloid leukemia (CML).

29. What are important environmental cancer risk factors?

👉 Tobacco smoke, ultraviolet radiation, occupational carcinogens, certain chemicals, and factors associated with obesity. They can cause DNA damage or contribute to cancer development.

30. What is loss of heterozygosity (LOH)?

👉 Loss or inactivation of the remaining functional allele of a tumor suppressor gene after the other allele is already altered, removing the cell’s remaining protection.