A 12-year-old boy presents with recurrent acute pancreatitis. His father and paternal grandfather both had a history of pancreatitis starting in childhood. Genetic testing confirms a gain-of-function mutation in the PRSS1 gene. The inheritance pattern marked **B** in the diagram best describes this family's condition. Which of the following statements about this inheritance pattern is most accurate?
A. X-linked recessive, affecting primarily males with carrier females remaining asymptomatic
B. Mitochondrial inheritance with maternal transmission and variable expression due to heteroplasmy
C. Autosomal dominant with incomplete penetrance (~80%), where affected individuals may have unaffected children despite carrying the mutation
D. Autosomal recessive, requiring two mutant alleles for disease manifestation in all carriers
Explanation
Why "Autosomal dominant with incomplete penetrance (~80%), where affected individuals may have unaffected children despite carrying the mutation" is right
Hereditary pancreatitis caused by PRSS1 mutations follows an autosomal dominant inheritance pattern with incomplete penetrance of approximately 80%. This means that not all individuals carrying the pathogenic mutation will develop clinical disease, and some mutation carriers may remain asymptomatic throughout life. The gain-of-function mutations in PRSS1 (most commonly R122H and N29I variants) enhance trypsinogen autoactivation or resist inactivation, leading to premature intra-pancreatic trypsin activation. The incomplete penetrance explains why this boy's father and grandfather are affected, but some family members carrying the same mutation may never develop pancreatitis (CAPS Consortium 2022; ACG Pancreatitis Guidelines 2024).
Why each distractor is wrong
Autosomal recessive, requiring two mutant alleles for disease manifestation in all carriers: PRSS1-related hereditary pancreatitis is autosomal dominant, not recessive. Autosomal recessive inheritance would require two mutant alleles and would show a different family pattern (typically unaffected parents with affected children). PRSS1 mutations are gain-of-function, requiring only one mutant allele.
X-linked recessive, affecting primarily males with carrier females remaining asymptomatic: X-linked inheritance does not fit this pedigree. The boy's father is affected, and fathers cannot pass X-linked traits to sons. Additionally, PRSS1 is located on chromosome 7q34, not the X chromosome.
Mitochondrial inheritance with maternal transmission and variable expression due to heteroplasmy: Mitochondrial inheritance would show maternal-only transmission (affected mothers pass to all children; affected fathers pass to none). This family shows paternal transmission (father to son), which excludes mitochondrial inheritance. PRSS1 is a nuclear gene, not mitochondrial.
High-YieldNEET PG
Hereditary pancreatitis (PRSS1) = autosomal dominant + incomplete penetrance (~80%) + gain-of-function mutations → some carriers remain asymptomatic; always counsel families about variable expressivity and screen relatives.
