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

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Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. / Renner, Sina; Schüler, 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; Altmüller, Janine; Wey-Fabrizius, Alexandra; Petersen, Christine; Rau, Isabella; Borck, Guntram; Kubisch, Christian; Mir, Thomas S; von Kodolitsch, Yskert; Kutsche, Kerstin; Rosenberger, Georg.

in: GENET MED, Jahrgang 21, Nr. 8, 08.2019, S. 1832-1841.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsätze › Forschung › Begutachtung

Harvard

Renner, S, Schüler, H, Alawi, M, Kolbe, V, Rybczynski, M, Woitschach, R, Sheikhzadeh, S, Stark, VC, Olfe, J, Roser, E, Seggewies, FS, Mahlmann, A, Hempel, M, Hartmann, MJ, Hillebrand, M, Wieczorek, D, Volk, AE, Kloth, K, Koch-Hogrebe, M, Abou Jamra, R, Mitter, D, Altmüller, J, Wey-Fabrizius, A, Petersen, C, Rau, I, Borck, G, Kubisch, C, Mir, TS, von Kodolitsch, Y, Kutsche, K & Rosenberger, G 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, Jg. 21, Nr. 8, S. 1832-1841. https://doi.org/10.1038/s41436-019-0435-z

APA

Renner, S., Schüler, H., Alawi, M., Kolbe, V., Rybczynski, M., Woitschach, R., Sheikhzadeh, S., Stark, V. C., Olfe, J., Roser, E., Seggewies, F. S., Mahlmann, A., Hempel, M., Hartmann, M. J., Hillebrand, M., Wieczorek, D., Volk, A. E., Kloth, K., Koch-Hogrebe, M., ... Rosenberger, G. (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), 1832-1841. https://doi.org/10.1038/s41436-019-0435-z

Vancouver

Renner S, Schüler H, Alawi M, Kolbe V, Rybczynski M, Woitschach R et al. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. GENET MED. 2019 Aug;21(8):1832-1841. https://doi.org/10.1038/s41436-019-0435-z

Bibtex

@article{8153f4f1c6d84864b16cd70f21ec3b87,
title = "Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients",
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 = "Adult, Aorta/metabolism, Biomarkers/metabolism, Cohort Studies, Connective Tissue/metabolism, Connective Tissue Diseases/genetics, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Male, Marfan Syndrome/diagnosis",
author = "Sina Renner and Helke Sch{\"u}ler and Malik Alawi and Verena Kolbe and Meike Rybczynski and Rixa Woitschach and Sara Sheikhzadeh and Stark, {Veronika C} and Jakob Olfe and Elke Roser and Seggewies, {Friederike Sophia} and Adrian Mahlmann and Maja Hempel and Hartmann, {Melanie J} and Mathias Hillebrand and Dagmar Wieczorek and Volk, {Alexander Erich} and Katja Kloth and Margarete Koch-Hogrebe and {Abou Jamra}, Rami and Diana Mitter and Janine Altm{\"u}ller and Alexandra Wey-Fabrizius and Christine Petersen and Isabella Rau and Guntram Borck and Christian Kubisch and Mir, {Thomas S} and {von Kodolitsch}, Yskert and Kerstin Kutsche and Georg Rosenberger",
year = "2019",
month = aug,
doi = "10.1038/s41436-019-0435-z",
language = "English",
volume = "21",
pages = "1832--1841",
journal = "GENET MED",
issn = "1098-3600",
publisher = "NATURE PUBLISHING GROUP",
number = "8",

}

RIS

TY - JOUR

T1 - Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

AU - Renner, Sina

AU - Schüler, Helke

AU - Alawi, Malik

AU - Kolbe, Verena

AU - Rybczynski, Meike

AU - Woitschach, Rixa

AU - Sheikhzadeh, Sara

AU - Stark, Veronika C

AU - Olfe, Jakob

AU - Roser, Elke

AU - Seggewies, Friederike Sophia

AU - Mahlmann, Adrian

AU - Hempel, Maja

AU - Hartmann, Melanie J

AU - Hillebrand, Mathias

AU - Wieczorek, Dagmar

AU - Volk, Alexander Erich

AU - Kloth, Katja

AU - Koch-Hogrebe, Margarete

AU - Abou Jamra, Rami

AU - Mitter, Diana

AU - Altmüller, Janine

AU - Wey-Fabrizius, Alexandra

AU - Petersen, Christine

AU - Rau, Isabella

AU - Borck, Guntram

AU - Kubisch, Christian

AU - Mir, Thomas S

AU - von Kodolitsch, Yskert

AU - Kutsche, Kerstin

AU - Rosenberger, Georg

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - Adult

KW - Aorta/metabolism

KW - Biomarkers/metabolism

KW - Cohort Studies

KW - Connective Tissue/metabolism

KW - Connective Tissue Diseases/genetics

KW - Female

KW - Genetic Testing

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Marfan Syndrome/diagnosis

U2 - 10.1038/s41436-019-0435-z

DO - 10.1038/s41436-019-0435-z

M3 - SCORING: Journal articles

C2 - 30675029

VL - 21

SP - 1832

EP - 1841

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 8

ER -