60. Human Genetics III | Mendelian Exceptions and Genomic Imprinting

A 42-year-old man develops progressive chorea, mood changes, and cognitive decline. Genetic testing shows CAG trinucleotide repeat expansion on chromosome 4 with paternal transmission. Which of the following best explains why his children may have earlier onset of symptoms?

A. Co-dominant inheritance of expanded alleles
B. Anticipation from repeat expansion
C. Pseudoautosomal inheritance of the HTT gene
D. Maternal uniparental disomy of chromosome 4
E. Mitochondrial heteroplasmy

B

• A. Co-dominant inheritance – Not correct; Huntington is autosomal dominant, not codominant.

• B. Anticipation – Correct. Repeat expansions worsen in successive generations, especially with paternal transmission in Huntington disease.

• C. Pseudoautosomal inheritance – Wrong; HTT gene is on chromosome 4, not in X/Y pseudoautosomal regions.

• D. Maternal uniparental disomy – Not relevant to Huntington.

• E. Mitochondrial heteroplasmy – Affects maternal inheritance, not applicable here.

A neonate with macrosomia and macroglossia is found to have paternal uniparental disomy of chromosome 11p15.5 involving the IGF2/H19 region. Which statement best predicts her future clinical risk profile?

A. Decreased risk of embryonal tumors due to loss of IGF2 expression
B. Increased risk of Wilms tumor and hepatoblastoma due to IGF2 overexpression
C. Increased risk of Prader-Willi syndrome due to paternal imprinting defects
D. No cancer risk because methylation defects silence growth genes
E. High risk of mitochondrial encephalopathy due to maternal heteroplasmy

B

• A. Decreased tumor risk – Opposite: IGF2 over-expression promotes overgrowth.

• B. Increased risk (✅) – Correct. Beckwith-Wiedemann syndrome results from dysregulation at 11p15.5 → ↑ IGF2 activity, ↓ H19/CDKN1C → macrosomia & tumor predisposition.

• C. Prader-Willi – Different chromosome (15).

• D. No cancer risk – Incorrect; overgrowth syndromes carry tumor risk.

• E. Mitochondrial – Unrelated.

Alkaptonuria is a disease in which the body cannot process amino acids properly. There are many different mutations in the same locus of a chromosome that can cause this disease. Which concept best describes this phenomenon?

A. Allelic heterogeneity

B. Codominance

C. Epistasis

D. Linkage

E. Locus heterogeneity

A

The correct answer is allelic heterogeneity (A). The question describes many mutations at the same locus causing alkaptonuria. Allelic heterogeneity happens when different mutations at the same location of a gene cause the same disease. Codominance (B) describes when two different alleles are both phenotypically expressed. Epistasis (C) refers to when one gene affects the expression of a different gene. Linkage (D) is the phenomenon by which certain genes are inherited together more often than others due to close proximity on chromosomes. Allelic and locus heterogeneity (E) can be confused; if the question had been referencing a disease caused by mutations at different loci, locus heterogeneity would be a reasonable answer.

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