A 28-year-old Ashkenazi Jewish couple presents for genetic counseling prior to conception. Carrier screening reveals that both partners are heterozygous for HEXA gene mutations. The pedigree diagram shows that **C** represents the expected proportion of affected children per pregnancy if both parents are carriers. What is the most appropriate counseling point regarding the risk of Tay-Sachs disease in their offspring, and what is the recommended next step?

Explanation

## Why option 1 is right When both parents are heterozygous (carriers) for an autosomal recessive condition like Tay-Sachs disease, the Mendelian inheritance pattern dictates that **C** — 25% of offspring per pregnancy — will be homozygous for the HEXA mutation and thus affected with the disease. The clinical anchor specifies that this 25% risk applies to affected children per pregnancy in carrier × carrier matings. Given the high carrier frequency in Ashkenazi Jewish populations (~1:27) and the severe neurological consequences of infantile Tay-Sachs (developmental regression, cherry-red spot, hyperacusis, death by age 4–5), prenatal diagnosis via amniocentesis or chorionic villus sampling (CVS) with enzyme assay or molecular testing is the standard-of-care recommendation to allow informed reproductive choice. This reflects the evidence-based public health approach that has dramatically reduced Tay-Sachs incidence in Ashkenazi communities (Harrison 21e Ch 471; Nelson 21e). ## Why each distractor is wrong - **Option 2**: Confuses the risk of carriers (50%) with the risk of affected offspring (25%). While 50% will be carriers, the counseling must emphasize the 25% risk of affected children — the critical clinical point. Prenatal diagnosis is absolutely indicated when both parents are carriers. - **Option 3**: Overstates the risk; 75% are either affected or carriers, but this conflates two different risk categories and misrepresents the Mendelian ratio. Genetic testing of all children is not standard practice — prenatal diagnosis is the recommended approach. - **Option 4**: Incorrectly states 100% inheritance of a mutant allele (only 75% inherit at least one) and falsely suggests enzyme replacement therapy can be given prenatally. ERT has limited efficacy in crossing the blood-brain barrier and is not standard prenatal management; supportive care and informed reproductive counseling are the standard approach. **High-Yield:** Ashkenazi Jewish carrier screening for Tay-Sachs is a public health imperative; both carrier parents face 25% risk of affected offspring per pregnancy — prenatal diagnosis is the standard counseling recommendation. [cite: Harrison 21e Ch 471; Nelson 21e]