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Whole-Exome Sequencing Identifies Mutation Signatures of Collagen-Containing Extracellular Matrix Genes in Polymelia

Polymelia is a rare congenital disease in humans characterized by extra limbs and a poorly understood etiology. To understand the mechanisms responsible for polymelia, DNA was isolated from two polymelia children with congenital malformations and their healthy parents for whole-exome sequencing. Using three hypothetical inheritance patterns and Ingenuity Pathway Analysis (IPA) the disease network analysis identified a network of Cancer, Connective Tissue Disorders, Organismal Injury and Abnormalities which included eleven mutated genes that might play roles in the proband multi-malformations. Variants in three collagen-associated genes, including rs146977141 c.5168 A > G and rs372335521 c.5207 C > T in COL27A1, c.1786_1794del and c.2106_2114del in COL18A1 and rs754836509 c.3940 C > T in COL4A5, were further validated. A significant defect of notochord was observedin both COL18A1 and COL4A5 morphants in zebrafish. Our results identified variants in collagen-containing extracellular matrix genes might be critical in the development of polymelia.