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Genome sequencing in families with congenital limb malformations

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Genome sequencing in families with congenital limb malformations. / Elsner, Jonas; Mensah, Martin A; Holtgrewe, Manuel; Hertzberg, Jakob; Bigoni, Stefania; Busche, Andreas; Coutelier, Marie; de Silva, Deepthi C; Elçioglu, Nursel; Filges, Isabel; Gerkes, Erica; Girisha, Katta M; Graul-Neumann, Luitgard; Jamsheer, Aleksander; Krawitz, Peter; Kurth, Ingo; Markus, Susanne; Megarbane, Andre; Reis, André; Reuter, Miriam S; Svoboda, Daniel; Teller, Christopher; Tuysuz, Beyhan; Türkmen, Seval; Wilson, Meredith; Woitschach, Rixa; Vater, Inga; Caliebe, Almuth; Hülsemann, Wiebke; Horn, Denise; Mundlos, Stefan; Spielmann, Malte.

In: HUM GENET, Vol. 140, No. 8, 08.2021, p. 1229-1239.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Elsner, J, Mensah, MA, Holtgrewe, M, Hertzberg, J, Bigoni, S, Busche, A, Coutelier, M, de Silva, DC, Elçioglu, N, Filges, I, Gerkes, E, Girisha, KM, Graul-Neumann, L, Jamsheer, A, Krawitz, P, Kurth, I, Markus, S, Megarbane, A, Reis, A, Reuter, MS, Svoboda, D, Teller, C, Tuysuz, B, Türkmen, S, Wilson, M, Woitschach, R, Vater, I, Caliebe, A, Hülsemann, W, Horn, D, Mundlos, S & Spielmann, M 2021, 'Genome sequencing in families with congenital limb malformations', HUM GENET, vol. 140, no. 8, pp. 1229-1239. https://doi.org/10.1007/s00439-021-02295-y

APA

Elsner, J., Mensah, M. A., Holtgrewe, M., Hertzberg, J., Bigoni, S., Busche, A., Coutelier, M., de Silva, D. C., Elçioglu, N., Filges, I., Gerkes, E., Girisha, K. M., Graul-Neumann, L., Jamsheer, A., Krawitz, P., Kurth, I., Markus, S., Megarbane, A., Reis, A., ... Spielmann, M. (2021). Genome sequencing in families with congenital limb malformations. HUM GENET, 140(8), 1229-1239. https://doi.org/10.1007/s00439-021-02295-y

Vancouver

Elsner J, Mensah MA, Holtgrewe M, Hertzberg J, Bigoni S, Busche A et al. Genome sequencing in families with congenital limb malformations. HUM GENET. 2021 Aug;140(8):1229-1239. https://doi.org/10.1007/s00439-021-02295-y

Bibtex

@article{6bcb99b4941747079d7d85110606c4f7,
title = "Genome sequencing in families with congenital limb malformations",
abstract = "The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.",
keywords = "Base Sequence, Cohort Studies, DNA Copy Number Variations, Gene Expression, Genetic Heterogeneity, Genetic Testing, Homeodomain Proteins/genetics, Humans, Infant, Limb Deformities, Congenital/genetics, Male, Mutation, Pedigree, Transcription Factors/deficiency, Ubiquitin-Activating Enzymes/deficiency, Whole Genome Sequencing",
author = "Jonas Elsner and Mensah, {Martin A} and Manuel Holtgrewe and Jakob Hertzberg and Stefania Bigoni and Andreas Busche and Marie Coutelier and {de Silva}, {Deepthi C} and Nursel El{\c c}ioglu and Isabel Filges and Erica Gerkes and Girisha, {Katta M} and Luitgard Graul-Neumann and Aleksander Jamsheer and Peter Krawitz and Ingo Kurth and Susanne Markus and Andre Megarbane and Andr{\'e} Reis and Reuter, {Miriam S} and Daniel Svoboda and Christopher Teller and Beyhan Tuysuz and Seval T{\"u}rkmen and Meredith Wilson and Rixa Woitschach and Inga Vater and Almuth Caliebe and Wiebke H{\"u}lsemann and Denise Horn and Stefan Mundlos and Malte Spielmann",
year = "2021",
month = aug,
doi = "10.1007/s00439-021-02295-y",
language = "English",
volume = "140",
pages = "1229--1239",
journal = "HUM GENET",
issn = "0340-6717",
publisher = "Springer",
number = "8",

}

RIS

TY - JOUR

T1 - Genome sequencing in families with congenital limb malformations

AU - Elsner, Jonas

AU - Mensah, Martin A

AU - Holtgrewe, Manuel

AU - Hertzberg, Jakob

AU - Bigoni, Stefania

AU - Busche, Andreas

AU - Coutelier, Marie

AU - de Silva, Deepthi C

AU - Elçioglu, Nursel

AU - Filges, Isabel

AU - Gerkes, Erica

AU - Girisha, Katta M

AU - Graul-Neumann, Luitgard

AU - Jamsheer, Aleksander

AU - Krawitz, Peter

AU - Kurth, Ingo

AU - Markus, Susanne

AU - Megarbane, Andre

AU - Reis, André

AU - Reuter, Miriam S

AU - Svoboda, Daniel

AU - Teller, Christopher

AU - Tuysuz, Beyhan

AU - Türkmen, Seval

AU - Wilson, Meredith

AU - Woitschach, Rixa

AU - Vater, Inga

AU - Caliebe, Almuth

AU - Hülsemann, Wiebke

AU - Horn, Denise

AU - Mundlos, Stefan

AU - Spielmann, Malte

PY - 2021/8

Y1 - 2021/8

N2 - The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

AB - The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

KW - Base Sequence

KW - Cohort Studies

KW - DNA Copy Number Variations

KW - Gene Expression

KW - Genetic Heterogeneity

KW - Genetic Testing

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Infant

KW - Limb Deformities, Congenital/genetics

KW - Male

KW - Mutation

KW - Pedigree

KW - Transcription Factors/deficiency

KW - Ubiquitin-Activating Enzymes/deficiency

KW - Whole Genome Sequencing

U2 - 10.1007/s00439-021-02295-y

DO - 10.1007/s00439-021-02295-y

M3 - SCORING: Journal article

C2 - 34159400

VL - 140

SP - 1229

EP - 1239

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 8

ER -