Renner, Sina, Schueler, Helke, Alawi, Malik, Kolbe, Verena, Rybczynski, Meike, Woitschach, Rixa, Sheikhzadeh, Sara, Stark, Veronika C., Olfe, Jakob, Roser, Elke, Seggewies, Friederike Sophia, Mahlmann, Adrian, Hempel, Maja, Hartmann, Melanie J., Hillebrand, Mathias, Wieczorek, Dagmar, Volk, Alexander Erich, Kloth, Katja, Koch-Hogrebe, Margarete, Abou Jamra, Rami, Mitter, Diana, Altmueller, Janine, Wey-Fabrizius, Alexandra, Petersen, Christine, Rau, Isabella, Borck, Guntram, Kubisch, Christian, Mir, Thomas S., von Kodolitsch, Yskert, Kutsche, Kerstin and Rosenberger, Georg (2019). Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet. Med., 21 (8). S. 1832 - 1842. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0366

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Renner, SinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schueler, HelkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alawi, MalikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolbe, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rybczynski, MeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woitschach, RixaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sheikhzadeh, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stark, Veronika C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olfe, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roser, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seggewies, Friederike SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahlmann, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hempel, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, Melanie J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillebrand, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volk, Alexander ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloth, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch-Hogrebe, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abou Jamra, RamiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitter, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wey-Fabrizius, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rau, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mir, Thomas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kodolitsch, YskertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutsche, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenberger, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-145968
DOI: 10.1038/s41436-019-0435-z
Journal or Publication Title: Genet. Med.
Volume: 21
Number: 8
Page Range: S. 1832 - 1842
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
THORACIC AORTIC-ANEURYSM; AMERICAN-COLLEGE; VARIANTS; MUTATION; GENETICS; DISSECTION; GUIDELINES; MANAGEMENT; DIAGNOSIS; MARFANMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14596

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