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Genet Med. 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.

Author information

1
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Centre of Cardiology and Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
3
Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4
Pediatric Cardiology Clinic, University Heart Center, Hamburg, Germany.
5
Klinik für Herz- und Gefäßkrankheiten, Klinikum Stuttgart-Katharinenhospital, Stuttgart, Germany.
6
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
University Centre for Vascular Medicine and Department of Medicine III-Section Angiology, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany.
8
Institute of Human Genetics, University of Ulm, Ulm, Germany.
9
Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
10
Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany.
11
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
12
Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
13
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. rosenberger@uke.de.

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

PMID:
30675029
DOI:
10.1038/s41436-019-0435-z

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