A 35-year-old Southeast Asian man is resuscitated from ventricular fibrillation that occurred during sleep. His 12-lead ECG shows coved-type ST-segment elevation ≥2 mm in leads V1–V2 with descending negative T-waves and incomplete right bundle branch block morphology. Echocardiography and cardiac MRI are normal. His father died suddenly during sleep at age 38, and his paternal uncle died suddenly at age 42. His older brother has Type 2 Brugada pattern that converted to Type 1 after ajmaline challenge. The inheritance pattern shown in the pedigree is marked as **A** in the diagram. Which of the following best describes the genetic and molecular basis of this inheritance pattern?
A. Autosomal dominant loss-of-function mutation in SCN5A (chromosome 3p21) encoding cardiac sodium channel Nav1.5, with male predominance (8:1 ratio) and low penetrance (~30%)
B. X-linked recessive mutation in SCN5A predominantly affecting males, with no male-to-male transmission and obligate carrier females
C. Autosomal recessive mutations in SCN5A affecting only siblings, with equal gender distribution and complete penetrance in heterozygotes
D. Mitochondrial inheritance through maternal transmission only, with variable expressivity due to heteroplasmy and no paternal contribution
Explanation
Why Autosomal dominant loss-of-function mutation in SCN5A is right
The clinical presentation—vertical transmission over multiple generations, male-to-male transmission (father to son, paternal grandfather to father), strong male predominance (8:1 ratio), 50% offspring risk with low penetrance (30%), and enrichment in Southeast Asian populations—is pathognomonic for autosomal dominant Brugada syndrome. Genetic testing in this patient confirms a heterozygous pathogenic loss-of-function mutation in SCN5A (chromosome 3p21), which encodes the cardiac sodium channel Nav1.5. This loss-of-function reduces inward sodium current (INa), creating a depolarization-repolarization mismatch in the right ventricular outflow tract epicardium that predisposes to phase 2 reentry and ventricular fibrillation, particularly during nocturnal vagal states, fever, large meals, and alcohol consumption. SCN5A accounts for 20–30% of Brugada cases and is the only well-validated major gene (Harrison's Principles of Internal Medicine, 21st ed., Chapter 251).
Why each distractor is wrong
Autosomal recessive mutations in SCN5A: Autosomal recessive inheritance would require two mutated alleles (homozygous or compound heterozygous) and would typically affect siblings equally without vertical transmission across generations. This pedigree shows clear vertical transmission and male-to-male transmission, which is incompatible with autosomal recessive inheritance.
X-linked recessive mutation in SCN5A: X-linked recessive inheritance would show no male-to-male transmission (affected fathers cannot pass X chromosome to sons), yet this pedigree demonstrates clear paternal transmission (grandfather → father → son). Additionally, X-linked recessive would not explain the high prevalence in males through the same mechanism as autosomal dominant with testosterone-mediated modulation.
Mitochondrial inheritance through maternal transmission only: Mitochondrial inheritance shows exclusively maternal transmission with no paternal contribution. This pedigree clearly demonstrates paternal transmission (father to son, grandfather to father), which excludes mitochondrial inheritance. Furthermore, mitochondrial mutations would not explain the Type 1 Brugada ECG pattern or the response to sodium channel modulators.
High-YieldNEET PG
Brugada syndrome is autosomal dominant with male predominance (8:1), caused by SCN5A loss-of-function mutations in ~25% of cases, and is enriched in Southeast Asian populations where it is recognized as "Lai-Tai" or "Bangungut" (nocturnal sudden death).
