A 12-year-old girl presents with syncope during swimming at summer camp. ECG shows QTc 510 ms with broad-based monophasic T-waves. Exercise stress testing reveals paradoxical QT prolongation. Her mother has borderline QTc (470 ms) and a family history of sudden cardiac death during exercise in multiple relatives over three generations. Genetic testing confirms a heterozygous KCNQ1 mutation. The inheritance pattern marked **A** in the diagram is most consistent with which of the following?
A. Autosomal dominant Romano-Ward syndrome with exercise-triggered syncope and vertical transmission
B. Mitochondrial inheritance with maternal transmission exclusively
C. X-linked recessive inheritance affecting only males in the pedigree
D. Autosomal recessive Jervell and Lange-Nielsen syndrome with congenital sensorineural deafness
Explanation
Why Autosomal dominant Romano-Ward syndrome with exercise-triggered syncope and vertical transmission is right
The clinical presentation and pedigree analysis definitively establish autosomal dominant inheritance (marked A). The key diagnostic features are: (1) vertical transmission across three generations (maternal grandfather → mother → patient), (2) male-to-male transmission is evident (maternal grandfather to mother's brother), (3) both sexes affected (males and females in the pedigree), (4) exercise-triggered events during swimming, which is pathognomonic for LQT1 caused by KCNQ1 loss-of-function mutations, and (5) heterozygous KCNQ1 mutation confirmed by genetic testing. The absence of congenital deafness excludes Jervell and Lange-Nielsen (autosomal recessive). The broad-based monophasic T-wave morphology and paradoxical QT prolongation with exercise are characteristic of LQT1. According to Harrison's Principles of Internal Medicine, Chapter 251, Romano-Ward syndrome is the autosomal dominant form of LQTS (40–55% of cases), typically caused by KCNQ1 mutations, with exercise (especially swimming) being the classic trigger for syncope.
Why each distractor is wrong
Autosomal recessive Jervell and Lange-Nielsen syndrome with congenital sensorineural deafness: This patient has normal hearing, which is a cardinal feature that excludes Jervell and Lange-Nielsen. Additionally, the pedigree shows male-to-male transmission (maternal grandfather to his son), which is impossible in autosomal recessive inheritance. Jervell and Lange-Nielsen accounts for only 1–5% of LQTS cases and requires homozygous mutations.
X-linked recessive inheritance affecting only males in the pedigree: The pedigree clearly shows affected females (the patient and her mother with borderline QTc), which rules out X-linked recessive inheritance. Furthermore, the maternal grandfather (a male) transmitted the trait to his daughter (the patient's mother), which is incompatible with X-linked recessive patterns.
Mitochondrial inheritance with maternal transmission exclusively: While the patient inherited the condition from her mother, the presence of male-to-male transmission (maternal grandfather to his offspring) definitively excludes mitochondrial inheritance, which permits only maternal transmission and would never show paternal-to-offspring transmission.
High-YieldNEET PG
Romano-Ward LQT1 = autosomal dominant KCNQ1 loss-of-function + exercise/swimming syncope + normal hearing; Jervell and Lange-Nielsen = autosomal recessive + congenital deafness (the key differentiator).
Harrison's Principles of Internal Medicine, 21st ed., Chapter 251: Inherited Arrhythmia Syndromes — Long QT Syndrome
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