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
N1 - Funding Information:
Open Access funding enabled and organized by Projekt DEAL. A.J. was supported by the grant from the Polish National Science Centre UMO-2016/22/E/NZ5/00270. M.S. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SP1532/3-1, SP1532/4-1 and SP1532/5-1), the Max Planck Foundation and the Deutsches Zentrum für Luft- und Raumfahrt (DLR 01GM1925).
Funding Information:
We would like to thank all families for their collaboration and contribution to this project. J.E. is supported by a scholarship of the Studienstiftung des deutschen Volkes e.V. M.A.M. is a participant in the BIH Charité Digital Clinician Scientist Program founded by the late Prof. Duska Dragun and funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.
Publisher Copyright:
© 2021, The Author(s).
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.
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U2 - 10.1007/s00439-021-02295-y
DO - 10.1007/s00439-021-02295-y
M3 - Article
AN - SCOPUS:85108660409
SN - 0340-6717
VL - 140
SP - 1229
EP - 1239
JO - Human Genetics
JF - Human Genetics
IS - 8
ER -