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...

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Autores principales:	Mario Torrado, Germán Fernández, Christian A. Ganoza, Emilia Maneiro, Diego García, Natalia Sonicheva-Paterson, Isaac Rosa, Juan Pablo Ochoa, Luis Santomé, Elena Vasichkina, Lorenzo Monserrat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/4ac6dfad532a4107bb331639ee65c964
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spelling	oai:doaj.org-article:4ac6dfad532a4107bb331639ee65c9642021-12-02T13:30:12ZA cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome10.1038/s41525-021-00183-y2056-7944https://doaj.org/article/4ac6dfad532a4107bb331639ee65c9642021-03-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00183-yhttps://doaj.org/toc/2056-7944Abstract 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.Mario TorradoGermán FernándezChristian A. GanozaEmilia ManeiroDiego GarcíaNatalia Sonicheva-PatersonIsaac RosaJuan Pablo OchoaLuis SantoméElena VasichkinaLorenzo MonserratNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Mario Torrado Germán Fernández Christian A. Ganoza Emilia Maneiro Diego García Natalia Sonicheva-Paterson Isaac Rosa Juan Pablo Ochoa Luis Santomé Elena Vasichkina Lorenzo Monserrat A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
description	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.
format	article
author	Mario Torrado Germán Fernández Christian A. Ganoza Emilia Maneiro Diego García Natalia Sonicheva-Paterson Isaac Rosa Juan Pablo Ochoa Luis Santomé Elena Vasichkina Lorenzo Monserrat
author_facet	Mario Torrado Germán Fernández Christian A. Ganoza Emilia Maneiro Diego García Natalia Sonicheva-Paterson Isaac Rosa Juan Pablo Ochoa Luis Santomé Elena Vasichkina Lorenzo Monserrat
author_sort	Mario Torrado
title	A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
title_short	A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
title_full	A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
title_fullStr	A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
title_full_unstemmed	A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome
title_sort	cryptic splice-altering kcnq1 variant in trans with r259l leading to jervell and lange-nielsen syndrome
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4ac6dfad532a4107bb331639ee65c964
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A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome

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