Journal Article

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

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

2019

Overview

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.

• Publisher: Nature Publishing Group US,Elsevier Limited
• Subject: Adult / Aneurysms / Aorta - metabolism / Aorta - physiopathology / Biomarkers - metabolism / Biomedical and Life Sciences / Biomedicine / Cardiology / Cohort Studies / Connective Tissue - metabolism / Connective Tissue - pathology / Connective Tissue Diseases - genetics / Connective Tissue Diseases - physiopathology / Disease / Dissection / Female / Genes / Genetic Testing / Genetics / Genomics / High-Throughput Nucleotide Sequencing / Human Genetics / Humans / Laboratory Medicine / Male / Marfan syndrome / Marfan Syndrome - diagnosis / Marfan Syndrome - genetics / Marfan Syndrome - physiopathology / Medicine / Mutation / Patients / Proteins