Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

Abstract

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

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

“…In this cohort of 810 patients, a pathogenic or likely pathogenic variant was identified in 66 patients (8.1%). Overall, we identified a relatively low number of pathogenic or likely pathogenic variants in our H-TAD cohort compared to pre-vious studies that identified mutations in 10.3% to 35.5% (Campens et al, 2015;Lerner-Ellis et al, 2014;Poninska et al, 2016;Proost et al, 2015;Wooderchak-Donahue et al, 2015;Ziganshin et al, 2015). This wide range is likely to be explained by differences in clinical and demographic characteristics of the study populations and different inclusion criteria used for genetic testing.…”

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

“…Increasingly extensive gene panels, as well as whole exome and genome sequencing, are used to interrogate the growing number of genes implicated in Mendelian diseases1. However, such panels only modestly increase the number of high-confidence diagnostic results while identifying ever larger numbers of variants of uncertain significance (VUS)2,3; these inconclusive results not only reduce the clinical utility of testing but can lead to mis-interpretation and mis-diagnosis.…”

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

“…Increasingly extensive gene panels are used to interrogate the growing number of genes implicated in Mendelian diseases (1). However, such panels only modestly increase the number of high-confidence diagnostic results while identifying ever larger numbers of variants of uncertain significance (VUS) (2)(3)(4). The likelihood that a rare variant is indeed pathogenic depends on the pre-test probability that the patient has the relevant disease.…”