Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip

Abstract

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.

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“…Therefore, the Ras/ERK pathway might is thought to play a significant role in the development of skeletal malformations during embryonic growth, based on emerging evidence. A family-based cohort study also observed mutations in SHC3 within the Ras/ERK pathway associated with the DDH phenotype (Dembic et al, 2023). This observation supports our findings and further substantiates the hypothesis of the critical role of the Ras/ERK pathway in embryonic skeletal development.…”

Environmental and Genetic Risk Factors in Developmental Dysplasia of the Hip for Early Detection of the Affected Population

“…The NGS analysis performed in our 15 patients with DDH revealed variants exclusively in the group of cases in the 18 analyzed genes. From the different 287 variants identified, ten have been previously associated with DDH, but these ten variants were found in cases and controls in our study population [12,13,31]. Among the 148 variants found exclusively in the group of cases, six have a MAF < 0.01 and a CADD > 20.…”

“…Several genome-wide association studies as well as targeted pathogenic variants analysis have been conducted recently. These studies have found an association of several variants in genes related to osteogenesis and joint formation, among other relevant biological processes [13,31].…”

“…Nevertheless, that aim is beyond the scope of the present work and will be the objective of future analysis. Some studies have found SNVs of interest after analyzing familial cases of DDH; segregation of these variants in affected individuals suggests a major role in the pathogenesis of the condition [31]. Nevertheless, more evidence is needed to consider the discovered variants as factors in the causal chain of events leading to DDH.…”

Deciphering the pathogenic role of rare RAF1 heterozygous missense mutation in the late-presenting DDH

“…Therefore, the Ras/ERK pathway might is thought to play a significant role in the development of skeletal malformations during embryonic growth, based on emerging evidence. A family-based cohort study also observed mutations in SHC3 within the Ras/ERK pathway associated with the DDH phenotype ( Dembic et al, 2023 ). This observation supports our findings and further substantiates the hypothesis of the critical role of the Ras/ERK pathway in embryonic skeletal development.…”