Genome sequencing in families with congenital limb malformations

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

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1229 - 1239
Number of pages11
JournalHuman Genetics
Issue number8
Publication statusPublished - 08-2021

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Genome sequencing in families with congenital limb malformations'. Together they form a unique fingerprint.

Cite this