Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

Abstract

Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients.

The etiology of VACTERL association: Current knowledge and hypotheses

“…For example, approximately 8% of reported results from GeneDx exomes (over 100,000 exome have been run in total, including currently >1,500 cases/month) are CNVs. Studies of cohorts affected by other conditions have identified significant rates of causative CNVs by next‐generation sequencing (NGS; Bergant et al, ; Overwater et al, ; Tsuchida et al, ). The detection of other structural variants as well as mosaicism by NGS, including from exome, genome, and targeted panels, is also improving (Stosser et al, ).…”

Phenotypic spectrum of TGFB3 disease‐causing variants in a Dutch‐French cohort and first report of a homozygous patient

“…No more than 50 patients carrying disease‐causing TGFB3 variants have been reported so far . Here, we described genetic and clinical data from 32 TGFB3 patients from 17 families including the first homozygous individual.…”

“…Given the rarity of the disorder, with no more than 50 cases described so far, a precise delineation of its phenotype is yet to be determined …”

Re: “Bicuspid Aortic Valve Associated Aortopathy: A Primer for Cardiac Anaesthesiologists”

“…Cusp plication techniques may involve wedge resection of the calcified raphe, primary cusp plication over the nodule of Arantius, 29 or oversewing of the free cusp edge and commissural plication (Cabrol sutures). 27,28,30,31 Pericardial patch repair of the valve is no longer recommended owing to poor durability and increased risk of valve failure. 24,27 Risk factors associated with recurring AI after BAV repair include commissural orientation <160˚, Siever's type 2 BAV, and preoperative aortic valve annular diameter >29 mm.…”

“…54 Pertaining to the "genetic theory" the earliest, and perhaps most important gene is NOTCH, 55 as mutations are known to cause BAV and other cardiovascular defects such as aneurysms. 31,55 Pluripotent stem cells with a NOTCH1 mutation show impaired differentiation into smooth muscle cells and endothelial cells. 56 Currently, in humans there are approximately 10 other genes that are known to contribute to isolated and syndromic BAV.…”