Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

Item Type:	Article
Title:	Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients
Creators Name:	Renner, S. and Schüler, H. and Alawi, M. and Kolbe, V. and Rybczynski, M. and Woitschach, R. and Sheikhzadeh, S. and Stark, V.C. and Olfe, J. and Roser, E. and Seggewies, F.S. and Mahlmann, A. and Hempel, M. and Hartmann, M.J. and Hillebrand, M. and Wieczorek, D. and Volk, A.E. and Kloth, K. and Koch-Hogrebe, M. and Abou Jamra, R.i and Mitter, D. and Altmüller, J. and Wey-Fabrizius, A. and Petersen, C. and Rau, I. and Borck, G. and Kubisch, C. and Mir, T.S. and von Kodolitsch, Y. and Kutsche, K. and Rosenberger, G.
Abstract:	PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.
Keywords:	Aortopathy, Connective Tissue Disorder, TAAD, Marfan Syndrome, Next-Generation Sequencing
Source:	Genetics in Medicine
ISSN:	1098-3600
Publisher:	Nature Publishing Group
Volume:	21
Number:	8
Page Range:	1832-1841
Date:	August 2019
Official Publication:	https://doi.org/10.1038/s41436-019-0435-z
PubMed:	View item in PubMed

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