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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 (<jats:italic>METTL21B<\/jats:italic>, <jats:italic>DIS3L2<\/jats:italic>, <jats:italic>PPP6R2<\/jats:italic>, and <jats:italic>TM4SF19<\/jats:italic>) 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 <jats:italic>DACH1<\/jats:italic>, <jats:italic>MYH10<\/jats:italic>, <jats:italic>NOTCH2, TBX4, EVC2<\/jats:italic>, <jats:italic>OTOG<\/jats:italic>, and <jats:italic>SHC3<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1007\/s00438-022-01980-5","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T15:23:58Z","timestamp":1669908238000},"page":"329-342","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip"],"prefix":"10.1007","volume":"298","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2505-6863","authenticated-orcid":false,"given":"Maja","family":"Dembic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"van Brakel Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Jakob","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Mechlenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjeld","family":"S\u00f8balle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Michael","family":"Hertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"1980_CR1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1542\/peds.105.4.896","volume":"105","author":"American Academy of Pediatrics","year":"2000","unstructured":"American Academy of Pediatrics (2000) Clinical practice guideline: early detection of developmental dysplasia of the hip. 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