Orofacial cleft (OC) is a common congenital anomaly in humans which has lifelong implications for affected individuals. This disorder can be classified as syndromic or non-syndromic depending on the presence or absence of additional physical or neurodevelopmental abnormalities respectively. Non-syndromic cleft is often non-familial in nature and has a complex aetiology while syndromic forms tend to be monogenic. Although individual OC-related syndromes have been frequently described in the medical literature, there has not been a comprehensive review across syndromes, thereby leaving a gap in our knowledge, which this paper aims to address. Six hundred and three patients with cleft-related HPO terms were identified within the Deciphering Developmental Disorders (DDD) study. Genes carrying pathogenic/likely pathogenic variants were identified and reviewed enabling a diagnostic yield of 36.5%. In total, 124 candidate genes for syndromic OC were identified, including 34 new genes that should be considered for inclusion in clinical clefting panels. Functional enrichment and gene expression analyses identified 3 key processes that were significantly over-represented in syndromic OC gene lists: embryonic morphogenesis, protein stability and chromatin organisation. Comparison with non-syndromic OC gene networks led us to propose that chromatin remodelling specifically contributes to the aetiology of syndromic OC. Disease-driven gene discovery is a valid approach to gene identification and curation of gene panels. Through this approach we have started to unravel common molecular pathways contributing to syndromic orofacial clefting.
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Wilson, KateNewbury, Dianne F.
Department of Biological and Medical Sciences
Year of publication: 2023Date of RADAR deposit: 2023-02-23
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