Search

A novel frameshift mutation in the KCNH2 gene for long QT syndrome type 2 (LQTS2) was identified after torsades des pointes ventricular tachycardia in a 49-year-old patient managed with octreotide and nadolol for an acute variceal bleed. In spite of removal of offending medications, and correction of underlying electrolyte abnormalities, the patient’s QT interval remained prolonged—at 521 ms—raising the suspicion of an underlying channelopathy. Genetic studies confirmed heterozygosity for a novel frameshift mutation for the KCNH2 gene, D896Rfs X79. We explore the pathogenicity and clinical impact of this variant mutation. Résumé: Une nouvelle mutation de changement de phase du gène KCNH2 impliqué dans le syndrome du QT long de type 2 (SQTL2) a été trouvée après une tachycardie ventriculaire à torsades de pointes chez un patient de 49 ans traité par octréotide et nadolol en raison d’un saignement variqueux en phase aiguë. En dépit du retrait des médicaments mis en cause et de la correction des anomalies électrolytiques sous-jacentes, l’intervalle du QT du patient qui demeurait prolongé (à 521 ms) a suscité la suspicion d’une canalopathie sous-jacente. Des études génétiques ont permis de confirmer l’hétérozygosité d’une nouvelle mutation de changement de phase du gène KCNH2, D896Rfs X79. Nous examinons la pathogénicité et les répercussions cliniques de cette mutation du variant.

To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5' to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular.