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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 <jats:italic>HOXD13<\/jats:italic>. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in <jats:italic>UBA2<\/jats:italic>, 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. 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The Charit\u00e9\u2019s ethic commission served as the central IRB.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Participants or their legal guardians provided written informed consent for participation in this study. Consents of all participants were archived. All published data has been pseudonymized, grouped where possible, and minimized.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Participants or their legal guardians provided written informed consent for pseudonymized publication of their data. Consents of all participants were archived. All published data have been pseudonymized, grouped where possible, and minimized.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}