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. 2019 Aug;21(8):1832-1841.
doi: 10.1038/s41436-019-0435-z. Epub 2019 Jan 24.

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

Sina Renner  1 , Helke Schüler  2 , Malik Alawi  3 , Verena Kolbe  1 , Meike Rybczynski  2 , Rixa Woitschach  1 , Sara Sheikhzadeh  2 , Veronika C Stark  4 , Jakob Olfe  4 , Elke Roser  5 , Friederike Sophia Seggewies  6 , Adrian Mahlmann  7 , Maja Hempel  1 , Melanie J Hartmann  8 , Mathias Hillebrand  2 , Dagmar Wieczorek  9 , Alexander Erich Volk  1 , Katja Kloth  1 , Margarete Koch-Hogrebe  10 , Rami Abou Jamra  11 , Diana Mitter  11 , Janine Altmüller  12 , Alexandra Wey-Fabrizius  1 , Christine Petersen  1 , Isabella Rau  1 , Guntram Borck  8 , Christian Kubisch  1 , Thomas S Mir  4 , Yskert von Kodolitsch  2 , Kerstin Kutsche  1 , Georg Rosenberger  13
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Free article

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

Sina Renner et al. Genet Med. 2019 Aug.
Free article

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: Marfan syndrome; TAAD; aortopathy; connective tissue disorder; next-generation sequencing.

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