The Otto Aufranc Award: Identification of a 4 Mb Region on Chromosome 17q21 Linked to Developmental Dysplasia of the Hip in One 18-member, Multigeneration Family

Abstract

Developmental dysplasia of the hip (DDH) is a disabling condition that, depending on geography, can afflict between 20% and 80% of patients with end-stage arthritis of the hip. Despite its prevalence, the etiology of this disease remains unknown. DDH is a complex disorder with both environmental and genetic causes. Based on the literature the candidate genes for the disease are HOXB9, collagen type I alpha1, and DLX 3. The purpose of our study was to map and characterize the gene or genes responsible for this disorder by family linkage analysis. We recruited one 18-member, multigeneration affected family to provide cheek swabs and blood samples for isolation of DNA. Amplified DNA underwent a total genome scan using GeneChip Mapping 250 K Assay (Affymetrix, Santa Clara, CA). We observed only one region with a LOD score greater than 1.5: a 4 Mb region on chromosome 17q21.32, yielding a LOD score of 1.82. While a LOD score of 1.82 does not meet the accepted standard for linkage we interpret these data as suggesting the responsible gene could be linked to this region, which includes a cluster of homeobox genes (HOX genes) that are part of the developmental regulatory system providing cells with specific positional identities along the developing joint and spine. Discovering the genetic basis of the disease would be an important step in understanding the etiology of this disabling condition.

Heritability and sibling recurrent risk of developmental dysplasia of the hip in Chinese population

“…This genetic model was further supported by Sollazzo et al [4] through a complex segregation analysis of 171 pedigrees. However, most of these loci have not been replicated in other population except for chromosome 17q21, which had been identified by Feldman et al [12] and our previous study [11]. Linkage analysis European Journal of Clinical Investigation Vol 43 589 DOI: 10.1111/eci.12084 ORIGINAL ARTICLE had also been attempted by different researchers to locate the causative genetic loci, and some possible susceptive loci had been implicated, such as chromosomes 4q35, 13q22, 16p and 17q21 [6,[9][10][11].…”

Biomechanics of foetal movement

“…It is thought that female babies are at higher risk due to their susceptibility to the maternal hormone relaxin, which may contribute to ligamentous laxity in the hip joint (Maclennan and Maclennan, 1997). There is limited information on what genes may be responsible for the familial incidence of DDH, with most studies proposing an association between a genetic or chromosome variant and DDH being focussed on individual families or single ethnicities (Dai et al, 2008;Feldman et al, 2010;Feldman et al, 2012;Hao et al, 2014;Rouault et al, 2010;Tian et al, 2012), limiting their impact on the wider population. However, evidence that GDF-5 may be linked with DDH has been revealed for both Chinese Han (Dai et al, 2008) and western Brittany (Rouault et al, 2010) patient groups.…”

Novel mutation in Teneurin 3 found to co‐segregate in all affecteds in a multi‐generation family with developmental dysplasia of the hip

“…It is not unusual to find examples of non‐penetrance in a complex disorder like DDH as environmental factors are known to affect the phenotype. Indeed, the DDH affected South African family studied by Roby and his colleagues and families investigated by other researchers have shown non‐penetrance …”

“…Evidence for a genetic cause is well established and includes a higher concordance between monozygotic (41%) than dizygotic (2.8%) twins, and a 12‐fold increase of DDH among first degree relatives of those affected by the disorder . DDH appears to be transmitted in an autosomal dominant fashion in several families and, perhaps because of its complex etiology, exhibits incomplete penetrance …”

“…12,13 DDH appears to be transmitted in an autosomal dominant fashion in several families and, perhaps because of its complex etiology, exhibits incomplete penetrance. 14,15 The goal of this study is to determine if DDH affected individuals, in a family that shows intergenerational transmission of this disorder, have novel mutation(s) or known genetic variants that make them susceptible to the disorder. In a previous study on a large multi-generation family, we identified a variant in the chemokine receptor CX3CR1 known to affect bone metabolism.…”