A 25-year-old nulligravid woman comes with her husband to the clinic for preconception genetic counseling. She has oculocutaneous albinism due to a homozygous OCA2 gene mutation within the region of chromosome 15q12-q13. Examination shows pale hypopigmented skin with blonde hair. Eye examination shows faint brown irises. Her husband is 26 years old and has oculocutaneous albinism due to a biallelic TYR gene mutation at position 11q14.3. Examination of the husband shows complete absence of pigmentation in the skin, hair, and irises. The couple asks about their chance of having a child with oculocutaneous albinism and are told that the chance is 0%. Which of the following is the best explanation for this?

Question

A 25-year-old nulligravid woman comes with her husband to the clinic for preconception genetic counseling.  She has oculocutaneous albinism due to a homozygous OCA2 gene mutation within the region of chromosome 15q12-q13.  Examination shows pale hypopigmented skin with blonde hair.  Eye examination shows faint brown irises.  Her husband is 26 years old and has oculocutaneous albinism due to a biallelic TYR gene mutation at position 11q14.3.  Examination of the husband shows complete absence of pigmentation in the skin, hair, and irises.  The couple asks about their chance of having a child with oculocutaneous albinism and are told that the chance is 0%.  Which of the following is the best explanation for this?

Quizplus · Accepted Answer

11ec160b_375e_beed_9249_c3194585b5c1_MD0001_00 This case is an example of locus heterogeneity, in which mutations at different genetic loci result in similar phenotypes. Both parents have oculocutaneous albinism, an inherited autosomal recessive disorder. However, although their phenotype is similar, their recessive mutations occur on different chromosomes. In this case, the child would inherit one normal (paternal) allele and one abnormal (maternal) allele at location 15q12-q13 and one normal (maternal) allele and one abnormal (paternal) allele at location 11q14.3. Because the child would have one normal, dominant allele at each location, they would be a double heterozygote and therefore would not express an oculocutaneous albinism phenotype. (Choice A) In contrast to this case, allelic heterogeneity describes different mutations at the same genetic locus causing similar phenotypes (eg, cystic fibrosis). Children born to parents who have autosomal recessive genetic conditions resulting from different mutations at the same genetic locus would inherit two abnormal copies of the gene and likely display the corresponding phenotype. (Choice B) Mitochondrial diseases (eg, MELAS syndrome, Leber hereditary optic neuropathy) are maternally inherited. The variable severity of these diseases is explained by heteroplasmy, the random distribution of normal and mutated mitochondrial DNA between daughter cells during meiosis. As a result, some eggs may have completely healthy mitochondria, while other cells contain mitochondria affected by genetic mutation. (Choice C) Penetrance is the probability that a person with a given genotype will express its associated phenotype. Incomplete penetrance means that some individuals with an abnormal genotype will not express the corresponding phenotype (eg, breast cancer in individuals with BRCA1/2 mutations). (Choice D) Two allele loci are said to be in linkage disequilibrium when a pair of alleles is inherited together in the same gamete (haplotype) more often or less often than would be expected given random pairing. This most often occurs when the genes are in close physical proximity on the same chromosome. (Choice F) The occurrence of multiple, seemingly unrelated phenotypic manifestations (often in different organ systems as a result of a single genetic defect) is termed pleiotrophy. Although this may apply to features of oculocutaneous albinism (eg, absence of melanin in skin, reduced visual acuity, nystagmus), it does not explain why a child of two affected parents would be unaffected. Educational objective: Locus heterogeneity describes when a similar phenotype is produced by mutations in different genetic loci (eg, oculocutaneous albinism).

A 25-Year-Old Nulligravid Woman Comes with Her Husband to the Clinic