A 3-year-old boy presents with recurrent pulmonary infections, failure to thrive, and pancreatic insufficiency. His parents are unaffected, but his younger sister has the same clinical presentation. The pedigree shows the pattern marked **A** — two unaffected carrier parents with 25% of offspring affected. Which of the following inheritance patterns and recurrence risks BEST describes this family's genetic status?

Explanation

## Why Autosomal recessive inheritance; 25% recurrence risk is right The pedigree pattern marked **A** is the hallmark of autosomal recessive (AR) inheritance: two unaffected carrier parents producing affected offspring (both siblings affected) with a 25% recurrence risk per pregnancy. In AR disorders like cystic fibrosis (CFTR mutation, chromosome 7q31), affected individuals are homozygous or compound heterozygous for the mutation, while carrier parents (heterozygotes) are phenotypically normal. When both parents are carriers (Aa × Aa), the Mendelian expectation is 25% affected (aa), 50% carrier (Aa), and 25% unaffected non-carrier (AA) offspring. The clinical presentation—recurrent pulmonary infections (Pseudomonas colonization), pancreatic insufficiency, and failure to thrive—is classic for cystic fibrosis, the most common AR disorder in Caucasian populations and increasingly recognized in Indian cohorts. The key diagnostic clue is HORIZONTAL CLUSTERING (siblings affected, parents unaffected), which is pathognomonic for AR inheritance. ## Why each distractor is wrong - **Autosomal dominant with incomplete penetrance**: AD inheritance typically shows VERTICAL clustering (parent-to-child transmission across generations). Unaffected parents do not produce affected children in AD unless de novo mutations occur (rare). The 50% recurrence risk applies when one parent is affected; here both parents are unaffected, ruling out AD. - **X-linked recessive**: XLR affects males predominantly and shows a characteristic pattern of affected males with carrier mothers. Affected females are rare (requires affected father + carrier mother). The fact that both male and female siblings are affected with unaffected parents fits AR better; XLR would predict carrier mother, not two unaffected parents. - **Mitochondrial inheritance**: Mitochondrial disorders show MATERNAL transmission exclusively (100% of offspring from affected mothers, 0% from affected fathers). The presence of an affected male with an unaffected mother contradicts mitochondrial inheritance. Additionally, both siblings being affected with unaffected parents is inconsistent with maternal-only transmission. **High-Yield:** Unaffected parents + multiple affected siblings of BOTH sexes + horizontal clustering = autosomal recessive; 25% recurrence risk when both parents are carriers. [cite: Nelson Pediatrics 21e Ch 99; Harrison 21e Ch 460]