Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with hypertrophic cardiomyopathy

Abstract

BackgroundHigh throughput sequencing technologies have revolutionized the identification of mutations responsible for genetic diseases such as hypertrophic cardiomyopathy (HCM). However, approximately 50% of individuals with a clinical diagnosis of HCM have no causal mutation identified. This may be due to the presence of pathogenic mutations located deep within the introns, which are not detected by conventional sequencing analysis restricted to exons and exon-intron boundaries.ObjectiveThe aim of this study was to develop a whole-gene sequencing strategy to prioritize deep intronic variants that may play a role in HCM pathogenesis.Methods and resultsThe full genomic DNA sequence of 26 genes previously associated with HCM was analysed in 16 unrelated patients. We identified likely pathogenic deep intronic variants in VCL, PRKAG2 and TTN genes. These variants, which are predicted to act through disruption of either splicing or transcription factor binding sites, are 3-fold more frequent in our cohort of probands than in normal European populations. Moreover, we found a patient that is compound heterozygous for a splice site mutation in MYBPC3 and the deep intronic VCL variant. Analysis of family members revealed that carriers of the MYBPC3 mutation alone do not manifest the disease, while family members that are compound heterozygous are clinically affected.ConclusionThis study provides a framework for scrutinizing variation along the complete intronic sequence of HCM-associated genes and prioritizing candidates for mechanistic and functional analysis. Our data suggest that deep intronic variation contributes to HCM phenotype.

Beyond the Big Five: Investigating Myostatin Structure, Polymorphism and Expression in Camelus dromedarius

“…Evidence about the existence of functional variants located in introns is growingly accumulating (Lee et al, 2015; Mou et al, 2015; Hong et al, 2018; Ostrovsky et al, 2018), not only restricted to exon–intron boundaries but also in deep intronic regions (Mendes de Almeida et al, 2017; Vaz-Drago et al, 2017). The three intronic SNPs detected in this study were in silico predicted to have the potential of altering both splicing and TFBS, thus suggesting they may play a role in myostatin processing and/or regulation.…”

Coverage and diagnostic yield of Whole Exome Sequencing for the Evaluation of Cases with Dilated and Hypertrophic Cardiomyopathy

“…Because of the lack of access to coverage data by the commercial gene panels, we were unable to have a direct comparison between WES and targetted gene sequencing. Moreover, the coverage of WES in the intronic region and for copy number of variations is poor, event though variants related to HCM and DCM have been reported in these regions 33 , 34 . Whether the use of whole genome sequencing can improve the diagnostic yield in HCM and DCM requires further study.…”

Повногеномний Пошук Асоціацій У Пацієнтів Української Популяції З Акромегалією

“…3, 4), для яких описано частоту, але не функцію. Глибокі інтронні мутації потребують подальшого вивчення, оскільки є дані про їх зв'язок із деякими захворюваннями [25].…”