Whole-exome analysis in pedigree of developmental dysplasia of the hip

Abstract

Objective Developmental dysplasia of the hip (DDH) is a complex disorder of hip joint affecting 1‰-5‰ of newborns.Despite unknown genetic impact on DDH, no functionally comparable genetic event has been found.Here we reported the variants contributing to DDH susceptibility in a family with four individuals affected across three generations. Methods Whole-exome sequencing was performed for three affected and two unaffected individuals of a DDH pedigree.Potential candidate variants were confirmed by Sanger sequencing and then validated in available family members. Results Not previously reported mutations were identified in two genes.One was protein-altering heterozygous, deletion or insertion mutation (c.1432_1440delCAGCAGCAG, p.Gln478_480del or c. 1440_1441insCAG, p.Gln480ins) in exon 11 of chromosome 4 in bone morphogenic proteins-2-inducible kinase (BMP2K) and another one termination codon mutation in exon 2/4 of chromosome 1 in prostaglandin F2α receptor (PTGFR). Both mutations in BMP2K and PTGFR were shared by DDH-affected members and unaffected grandmother deemed to be a carrier of potential mutations but not by unaffected normal control aunt.Mutations were present in 4/4 (100%) of affected family members, 3/12 (25%) of unaffected related family members and 0/8 (0%) of unaffected unrelated family members by Sanger sequencing. Conclusions BMP2K and PTGFR variants are probably DDH susceptibility inducing candidates.And a combination of pedigree information and next generation sequencing is effective for identifying pathogenic sites associated with DDH. Key words: Dysplasia of the hip; Exome; Sequencing; Gene mutation; Susceptible gene