A 7-year-old boy is brought to the pediatric cardiology clinic after experiencing a syncopal episode while swimming at school. His parents report that he failed newborn hearing screening bilaterally and has required hearing aids since infancy. On examination, he is found to have bilateral profound sensorineural hearing loss. An ECG shows a QTc interval of 560 ms with broad-based T waves. The audiogram and cardiac findings are consistent with the pattern marked **B** in the diagram. Which of the following genetic mutations is most likely responsible for this clinical presentation?

Question

Accepted Answer

D. Homozygous loss-of-function mutation in KCNQ1 encoding the α-subunit of the slow delayed rectifier potassium channel (IKs). ## Why option 1 is correct

The clinical triad of bilateral profound congenital sensorineural hearing loss, syncope triggered by exercise (swimming), and prolonged QTc interval (560 ms) is pathognomonic for Jervell and Lange-Nielsen Syndrome (JLNS). The pattern marked **B** in the diagram represents this exact phenotype. JLNS is caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in KCNQ1 (JLN1, ~90% of cases) or KCNE1 (JLN2, ~10%). These genes encode the α and β subunits, respectively, of the slow delayed rectifier potassium channel (IKs). Loss of functional IKs channels impairs both cardiac repolarization (causing long QT and syncope from torsades de pointes) and K+ secretion into the cochlear endolymph by stria vascularis marginal cells, resulting in cochlear degeneration and profound bilateral congenital deafness. This is an autosomal recessive condition; the parents are obligate heterozygous carriers with Romano-Ward syndrome phenotype (autosomal dominant LQT1 with normal hearing).

## Why each distractor is wrong

- **Option 2 (KCNH2/hERG)**: KCNH2 mutations cause Romano-Ward syndrome (autosomal dominant LQT2) with normal hearing. They do not produce the bilateral profound congenital sensorineural hearing loss seen in **B**, and are inherited in an autosomal dominant pattern, not recessive.
- **Option 3 (SCN5A)**: SCN5A mutations cause Brugada syndrome and autosomal dominant LQT3 (Romano-Ward). They do not account for the congenital bilateral profound deafness that is the hallmark of the **B** phenotype.
- **Option 4 (CACNA1C)**: CACNA1C mutations cause Timothy syndrome (autosomal dominant LQT8) with syndromic features (autism spectrum, immune deficiency, webbing), not the isolated combination of congenital deafness and long QT seen in **B**.

**High-Yield:** Bilateral profound congenital SNHL + syncope on exercise + long QT = JLNS (KCNQ1/KCNE1 biallelic); parents have Romano-Ward with normal hearing.

[cite: Nelson Pediatrics 22e (LQTS); GeneReviews — JLNS; Harrison's 21e]

Answer

A. Compound heterozygous mutations in CACNA1C encoding the L-type calcium channel

Answer

B. Heterozygous gain-of-function mutation in KCNH2 encoding the hERG potassium channel

Answer

C. Autosomal dominant mutation in SCN5A encoding the cardiac sodium channel

Explanation

Why option 1 is correct

Why each distractor is wrong

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