A 4-year-old girl presents to pediatric genetics with developmental regression, severe behavioral disturbance, and progressive loss of language skills that began after age 2 years. Her 2-year-old sister is currently asymptomatic but molecular testing confirms she carries the same biallelic pathogenic variants. Both parents are phenotypically normal and heterozygous carriers. Enzyme assay shows markedly deficient heparan-N-sulfatase (SGSH) activity, confirming Sanfilippo syndrome type A. A three-generation pedigree is constructed showing affected females in the same sibship, unaffected parents, and no sex-linked or maternal-only pattern. The inheritance pattern marked **A** in the diagram is most consistent with which of the following?
A. Autosomal dominant inheritance with variable expressivity
B. Autosomal recessive inheritance with 25% recurrence risk in future pregnancies
C. X-linked recessive inheritance with affected males predominantly
D. Mitochondrial inheritance with maternal transmission pattern
Explanation
Why Autosomal recessive inheritance with 25% recurrence risk in future pregnancies is right
Sanfilippo syndrome type A (MPS IIIA) is caused by biallelic pathogenic variants in the SGSH gene located on chromosome 17q25.3, inherited in an autosomal recessive pattern. The clinical presentation—two affected sisters born to phenotypically normal, heterozygous carrier parents—is the classic hallmark of autosomal recessive inheritance. The pedigree shows horizontal clustering within a sibship (both daughters affected), no sex predilection (both affected are female, but this is chance), no vertical transmission from affected parents, and no maternal-only pattern. The 25% recurrence risk for future pregnancies reflects the 1 in 4 probability when both parents are heterozygous carriers (Aa × Aa → 1 AA : 2 Aa : 1 aa). This inheritance pattern is explicitly documented in the Valstar et al. reference as the genetic basis of Sanfilippo syndrome.
Why each distractor is wrong
X-linked recessive inheritance with affected males predominantly: Sanfilippo syndrome is not X-linked; the SGSH gene is on chromosome 17, not the X chromosome. X-linked recessive conditions typically affect males more severely and show a pattern of affected males with carrier mothers, which is not present here.
Autosomal dominant inheritance with variable expressivity: Autosomal dominant inheritance would require at least one affected parent to pass the mutation to the affected child. Both parents are phenotypically normal and confirmed as heterozygous carriers, not homozygous affected individuals. Autosomal dominant conditions show vertical transmission across generations, which is absent in this pedigree.
Mitochondrial inheritance with maternal transmission pattern: Mitochondrial inheritance shows exclusive maternal transmission—all children of an affected mother are affected, and affected fathers do not transmit the condition. This pedigree shows transmission from both parents (both contributed one allele) and is not sex-specific, ruling out mitochondrial inheritance.
High-YieldNEET PG
Sanfilippo syndrome (MPS IIIA) is autosomal recessive; affected siblings with unaffected carrier parents is the classic presentation, with 25% recurrence risk per pregnancy.
Valstar MJ, Ruijter GJG, van Diggelen OP, et al. Sanfilippo syndrome: A mini-review. J Inherit Metab Dis. 2008;31(2):240-252.
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