Whole genome SNP genotyping in a family segregating developmental dysplasia of the hip detected runs of homozygosity on chromosomes 15q13.3 and 19p13.2

Abstract

Developmental dysplasia of the hip (DDH) is one of the most prevalent developmental orthopedic diseases worldwide. DDH is a spectrum of anatomical abnormalities of the hip joint and is characterized by premature arthritis in later life. Sporadic cases have been reported more frequently; however, some studies have reported families segregating DDH. Studies have suggested that the genetic factors play a significant role in the development of DDH. In order to detect genetic defect underlying DDH, we performed Sanger sequencing of all DDH associated genes, whole genome SNP genotyping and exome sequencing in a Saudi family with four individuals having DDH. Sanger sequencing of all known genes did not identify any pathogenic variant. Genotype data analysis using HomozygosityMapper identified shared homozygous regions on chromosome 15q13.3 and chromosome 19p13.2 flanked by rs17228178-rs1534200 and rs466123-rs2112461, respectively. These data were also analyzed by cnvpartition software for identification of DDH associated copy number variations (CNV). A shared copy number gain of approximately 15 kb on chr6p21.32 (chr6:33 053 906-33 069 893) was discovered in all affected individuals. Partial gain of this region has also been found in unaffected sibling of this family. Exome data did not reveal any candidate sequence variant. Whole genome sequencing is required to identify deep intronic variants in the shared homozygous regions. Identification of genetic variants involved in pathogenesis of DDH may open up interesting perspectives into the function of the gene(s) in hip joint development.

Mapping of developmental dysplasia of the hip to two novel regions at 8q23‑q24 and 12p12

“…Genetic mutations, such as CX3CR1, UFSP2, ubiquinol-cytochrome-c reductase complex, PAPPA2, GDF5 and TENM3, were identified in these regions. The present results and previously identified chromosome regions may be related to the growing development of the hip joint according to the function of genes included in these regions (10,12,13,(19)(20)(21)(22). DDH was previously associated with the D17S1820 marker from chromosome region 17q21 by analysing 303 individuals from 101 Chinese trios (data not shown).…”

Developmental dysplasia of the hip: a systematic literature review of the genes related with its occurrence

“…CX3CR1, HSPG2 and ATP2B4 genes have been highlighted by such studies so far. 2 Briefly, these candidate genes related with DDH are classified in Table 1.…”

“…Developmental dysplasia of the hip (DDH), also known by the preceding term congenital dislocation of the hip (CDH), is one of the most prevalent congenital malformations. 1,2 DDH has a wide spectrum of anatomical abnormalities of the hip joint and is characterized by mild or incomplete formation of the acetabulum, leading to laxity of the joint capsule, secondary deformity of the proximal femur and irreducible hip dislocation. 3 The leading cause of osteoarthritis of the hip in young individuals is undetected hip dysplasia.…”

“…1,4 Breech presentation, oligohydramnios, female gender, large birth weight and primiparity may play a role in the occurrence of DDH. 2 The condition may often affect multiple individuals in a single family through generations and a 12-fold increase of DDH among first-degree relatives of those affected by the disorder has been noticed. A large Chinese cohort study proved that there is a high sibling recurrent risk of DDH in the Asian population, with female siblings having double the risk in comparison with male siblings.…”

Developmental Dysplasia of Hip: Perspectives in Genetic Screening

“…Many genes of interest have been found to be associated with DDH such as COL1A1, GDF5, HOXB9, ASPN, VDR, IL6-gene, and HOXD9 [6,10,17,18,19,20,21,22]. Those genes are found to help the bone formation and chondrogenesis in large case-control studies among the Chinese and Caucasian populations (Table 1).…”