A 38-year-old Indian male presents with a 2-year history of flank pain and hypertension (BP 152/94 mmHg). Renal ultrasound shows multiple bilateral renal cysts. His father and paternal grandfather both had chronic kidney disease requiring dialysis. The pedigree pattern shown in the diagram is consistent with the inheritance pattern marked **A**. Which of the following genetic mutations is MOST LIKELY responsible for his disease and carries the HIGHEST risk for early end-stage renal disease?
A. DNAJB11 mutation associated with congenital hepatic fibrosis
B. GANAB mutation causing a milder phenotype with later renal failure
C. PKD1 mutation on chromosome 16, encoding polycystin-1 — ESRD typically by age 55-60
D. PKD2 mutation on chromosome 4, encoding polycystin-2 — ESRD typically by age 70-75
Explanation
Why PKD1 mutation on chromosome 16, encoding polycystin-1 — ESRD typically by age 55-60 is right
The pedigree pattern marked A shows autosomal dominant inheritance with vertical transmission across generations (father and paternal grandfather affected), which is classic for ADPKD. PKD1 mutations account for approximately 78% of ADPKD cases and are associated with earlier progression to ESRD (typically by age 55–60 years). PKD2 mutations (15% of cases) cause a milder phenotype with later ESRD onset (age 70–75). The patient's presentation with early-onset hypertension and flank pain in his late 30s, combined with a strong family history of early renal failure, is most consistent with PKD1 disease. According to KDIGO ADPKD guidelines and the TEMPO 3:4 trial, PKD1 mutations are the most common cause of ADPKD and account for 5–10% of all ESRD cases.
Why each distractor is wrong
PKD2 mutation on chromosome 4, encoding polycystin-2 — ESRD typically by age 70–75: While this is a genuine ADPKD gene, it accounts for only ~15% of cases and causes a significantly milder phenotype with later ESRD onset. The patient's strong family history of early renal failure (father and grandfather both requiring dialysis) is more consistent with PKD1.
GANAB mutation causing a milder phenotype with later renal failure: GANAB and other minor genes (DNAJB11, etc.) account for <5% of ADPKD cases and are rare. They do not fit the classical autosomal dominant pedigree pattern as commonly as PKD1/PKD2.
DNAJB11 mutation associated with congenital hepatic fibrosis: DNAJB11 is a rare cause of ADPKD and is more often associated with congenital hepatic fibrosis rather than pure ADPKD. It is not the most likely diagnosis in this classic presentation.
High-YieldNEET PG
PKD1 mutations (chromosome 16, 78% of ADPKD) cause ESRD by age 55–60; PKD2 mutations (chromosome 4, 15%) cause milder disease with ESRD by age 70–75. Both encode calcium-permeable cation channels on primary cilia; loss of function disrupts mechanosensation and calcium signalling, driving cyst formation.
KDIGO ADPKD Guideline 2025; TEMPO 3:4 trial NEJM 2012
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