A 6-year-old boy of Ashkenazi Jewish descent presents with severe growth retardation (height and weight <3rd percentile), a long narrow face with prominent nose, and a sun-sensitive erythematous telangiectatic rash in a butterfly distribution over the malar regions. He has recurrent upper respiratory infections and café-au-lait spots. His pedigree shows an affected younger sister, unaffected non-consanguineous parents, and no affected ancestors. Cytogenetic analysis reveals a dramatically increased rate of sister chromatid exchanges (approximately 10-fold higher than normal) and quadriradial chromosome figures. The inheritance pattern shown in the pedigree (marked **A** in the diagram) is consistent with which of the following genetic mechanisms?
A. Autosomal recessive inheritance with biallelic loss-of-function mutations in the BLM gene on chromosome 15q26.1
B. X-linked dominant inheritance with male lethality
C. Autosomal dominant inheritance with variable expressivity due to incomplete penetrance
D. Mitochondrial maternal inheritance with heteroplasmy
Explanation
Why autosomal recessive inheritance with biallelic loss-of-function mutations in the BLM gene on chromosome 15q26.1 is right
Bloom syndrome is an autosomal recessive chromosomal breakage/instability disorder caused by biallelic loss-of-function mutations in the BLM gene on chromosome 15q26.1. The pedigree pattern marked A in the diagram—affected siblings (boy and younger sister) with unaffected non-consanguineous parents and equal sex distribution—is the classic hallmark of autosomal recessive inheritance. In Ashkenazi Jews, a founder mutation (blmAsh) accounts for most cases, with a carrier frequency of approximately 1 in 100. The BLM protein is a RecQ family DNA helicase essential for resolving homologous recombination intermediates and maintaining genomic stability. Biallelic mutations result in defective DNA repair, leading to the characteristic 10-fold increase in sister chromatid exchanges and quadriradial chromosome figures observed on cytogenetic analysis (Cunniff et al., GeneReviews — Bloom Syndrome).
Why each distractor is wrong
Autosomal dominant inheritance with variable expressivity: Autosomal dominant conditions typically affect one parent and show vertical transmission across generations. In this pedigree, both parents are unaffected, ruling out dominant inheritance. Additionally, autosomal dominant disorders do not produce the characteristic pattern of two affected siblings from unaffected parents.
X-linked dominant inheritance with male lethality: X-linked dominant conditions with male lethality would present with affected females and no affected males, or affected males with severely affected/lethal manifestations in heterozygous females. This pedigree shows an affected male and affected female sibling, and the equal sex distribution contradicts X-linked inheritance.
Mitochondrial maternal inheritance with heteroplasmy: Mitochondrial inheritance shows maternal transmission exclusively—all children of an affected mother are affected, and no children of affected fathers are affected. This pedigree shows unaffected parents with affected children, which is incompatible with maternal inheritance. Additionally, mitochondrial disorders do not present with the cytogenetic hallmark of increased sister chromatid exchanges.
