A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome

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.

Splicing Outcomes of 5′ Splice Site GT>GC Variants That Generate Wild-Type Transcripts Differ Significantly Between Full-Length and Minigene Splicing Assays

“…RNA analysis using either patient blood cells or immortalized lymphoblastoid cells represents an alternative option, providing that the gene of interest is normally expressed in these cells (Wai et al, 2020). In case of the non-feasibility of both approaches, a cell culture-based minigene splicing assay has often been devised (for some most recent examples, see Damasio et al, 2021;Hao et al, 2021;Kim et al, 2021;Kortum et al, 2021;Le Tertre et al, 2021;Morbidoni et al, 2021;Qian et al, 2021;Saint-Martin et al, 2021;Torrado et al, 2021).…”

First report of genetic variants detected in Argentinian patients with clinical Long QT Syndrome diagnosis

“…This result may explain QT interval prolongation observed on the ECG scan. There is not much literature about exon 16 deletion but some authors have reported that young patients with deletions in exon 15 and 16 showed prolonged QTc 13,14 . Importantly, a small domain between residues 589 and 620 (i. e. within exon 16) in the KCNQ1 c-terminus may function as an assembly domain for KCNQ1 subunits 15 .…”

Suppression of P2X7R by Local Treatment Alleviates Acute Gouty Inflammation

“…29,30 The genetic mutations of KCNQ1 gene have been reported to be related to type 2 diabetes, 31 cardiovascular diseases 32 and deafness. 33,34 Thus far, only a GWAS research of Han Chinese found a correlation of KCNQ1 variants with gout while not hyperuricemia, 14 which mechanisms supposed be responsible of immune regulation. The amplification of inflammation of KCNQ1 blocker intervention in our gout mouse model was consistent with the hypothesis that KCNQ1 mediates gouty inflammation.…”