Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip.
Maja DembicLars van Brakel AndersenMartin Jakob LarsenInger MechlenburgKjeld SøballeJens Michael HertzPublished in: Molecular genetics and genomics : MGG (2022)
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.
Keyphrases
- genome wide
- extracellular matrix
- total hip arthroplasty
- copy number
- end stage renal disease
- mitochondrial dna
- bioinformatics analysis
- genome wide identification
- ejection fraction
- newly diagnosed
- chronic kidney disease
- risk factors
- prognostic factors
- gene expression
- peritoneal dialysis
- cell proliferation
- genome wide analysis
- patient reported outcomes
- atrial fibrillation
- single molecule
- data analysis
- deep learning
- density functional theory
- binding protein