Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia

Journal of Medical Genetics
Whitney L Wooderchak-DonahuePinar Bayrak-Toydemir

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich 'hotspot' region of ACVRL1intron 9 that disrupted splicing. Despite the diff...Continue Reading

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Citations

Aug 11, 2019·Molecular Genetics & Genomic Medicine·Yali ZhaoLuo Zhang
Apr 18, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jamie McDonaldKevin Whitehead
Nov 6, 2018·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·A BergougnouxM Taulan-Cadars
Mar 8, 2021·Clinical and Experimental Otorhinolaryngology·Bo-Gyeong KimSeon-Tae Kim

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