Genetics of developmental dysplasia of the hip: Recent progress and future perspectives

Abstract

Developmental dysplasia of the hip (DDH) is the most common congenital orthopedic disorder in infants. DDH is a heterogeneous disorder, and the exact pathophysiology is incompletely understood; however, several environmental as well as genetic factors have been identified as an underlying player in its pathogenesis. Involvement of genetic factors in the pathogenesis is evident from the fact that DDH occurrence has been observed in families with multiple affected individuals. Here, we reviewed the current literature on DDH, specifically concentrating on the genetic aspects of isolated (nonsyndromic) form of DDH. It is observed that genetic association studies, as well as linkage study designs, have been used to identify the extent of involvement of genetic factors in DDH pathogenesis. Variants in genes involved in joint development and chondrogenesis including HOXD9, ASPN, HOXB9, TGF-Beta 1, PAPPA2, DKK1, and GDF5 genes have been identified as associated with DDH through genetic association studies. Moreover, mutations in CX3CR1 and TENM3 have been identified using linkage analysis and exome sequencing. Although various approaches including association studies, linkage analysis, and targeted sequencing have been used to detect genetic factors underlying DDH, structural genetic variants underlying DDH have not been explored. Therefore, we propose that copy number variation analysis and interactome studies (interaction analysis using gene and protein data using molecular interaction search tools) can help in identifying new DDH-associated genes.