Abstract
Here we report an infant with clinical findings suggestive of Jervell and Lange-Nielsen syndrome (JLNS), including a prolonged QT interval (LQTS) and chronic bilateral sensorineural deafness. NGS analysis revealed one known heterozygous pathogenic missense variant, KCNQ1 p.R259L, previously associated with LQTS but insufficient to explain the cardioauditory disorder. In a screening of proximal intronic regions, we found a heterozygous variant, KCNQ1 c.1686−9 T > C, absent from controls and previously undescribed. Several splicing prediction tools returned low scores for this intronic variant. Driven by the proband’s phenotype rather than the neutral predictions, we have characterized this rare intronic variant. Family analysis has shown that the proband inherited the missense and the intronic variants from his mother and father, respectively. A minigene splicing assay revealed that the intronic variant induced an additional transcript, arising from skipping of exon 14, which was translated into a truncated protein in transfected cells. The splice-out of exon 14 creates a frameshift in exon 15 and a stop codon in exon 16, which is the last exon of KCNQ1. This mis-spliced transcript is expected to escape nonsense-mediated decay and predicted to encode a truncated loss-of-function protein, KCNQ1 p.L563Kfs*73. The analysis of endogenous KCNQ1 expression in the blood of the proband’s parents detected the aberrant transcript only in the patient’s father. Taken together, these analyses confirmed the proband’s diagnosis of JLNS1 and indicated that c.1686−9 T > C is a cryptic splice-altering variant, expanding the known genetic spectrum of biallelic KCNQ1 variant combinations leading to JLNS1.
Highlights
Jervell and Lange-Nielsen syndrome (JLNS) is a recessive cardioauditory disorder characterized by long QT syndrome (LQTS) associated with severe bilateral sensorineural hearing loss
Genetic diagnosis of JLNS is relevant for appropriate patient management, taking into account that Jervell and LangeNielsen syndrome 1 (JLNS1) patients with KCNQ1 variants are at higher risk, whereas KCNE1 variants in JLNS2 patients are associated with a more benign course
The deep learning-based tool to identify splice variants SpliceAI returned only a very low score for the delta score acceptor loss (Supplementary Fig. 2). Contrary to these in silico predictions and driven by the patient’s phenotype instead, we have considered that the rare KCNQ1 c.1686−9 T > C variant could be a suitable candidate if two criteria are met: first, be present in compound heterozygosity with p.R259L, and second, be able to affect RNA splicing in experimental assays
Summary
Jervell and Lange-Nielsen syndrome (JLNS) is a recessive cardioauditory disorder characterized by long QT syndrome (LQTS) associated with severe bilateral sensorineural hearing loss. This rare condition, affecting 3–5 in one million children[1], is caused by loss-of-function biallelic variants in the KCNQ1 gene (90.5% of cases2), leading to JLNS type 1 (JLNS1, OMIM 220400), or in the KCNE1 gene (9.5% of cases), leading to a similar syndrome known as JLNS2 (OMIM 612347). Genetic diagnosis of JLNS is relevant for appropriate patient management, taking into account that JLNS1 patients with KCNQ1 variants are at higher risk, whereas KCNE1 variants in JLNS2 patients are associated with a more benign course. In the largest JLNS study population[2], it was found that JLNS1 patients had 6-fold greater risk of arrhythmic events than JLNS2 patients
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