Genome sequencing in families with congenital limb malformations

Girisha, KM (2021) Genome sequencing in families with congenital limb malformations. Human Genetics, 140 (8). pp. 1229-1239. ISSN 0340-6717

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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 identifed 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 identifed likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identifed likely causative variants in three novel high confdence 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 identifed.

Item Type: Article
Subjects: Medicine > KMC Manipal > Medical Genetics
Depositing User: KMC Library
Date Deposited: 25 Aug 2021 08:34
Last Modified: 12 May 2022 04:47

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