Next generation sequencing increases precise diagnoses in non-syndromic cleft lip and/or palate

Cleft of the lip and/or palate (CLP) are among the most common birth defects. Affected children need multidisciplinary treatment and care from birth until adulthood. They most commonly occur as an isolated defect and have a complex and heterogeneous etiology with genetic predisposition as well as environmental factors acting in concert. Whole Exome Sequencing (WES) has now become a useful approach for proving clinical molecular diagnosis. We conducted WES in 79 non-syndromic (ns) CLP multiplex families to identify rare causing variants. Among families studied, seven were found to be mutated (~10%) in syndromic genes: TP63, TBX1, LRP6, GRHL3 and TBX22 providing further evidence of contribution of syndromic CLP genes in ns forms. Unraveling TBX22 mutations in 2 families allowed us to describe a new clinical oral sign: bony overgrowths on the posterior edge of the hard palate, on each side of the palatal midline, as well as to expand the TBX22-related phenotypic spectrum to choanal atresia and Pierre-Robin sequence. We also described mutations in a new gene, LRRC1 in 2 distinct families: one with Van der Woude syndrome and one with ns cleft palate. We then focused on a distinguishable CLP phenotype and performed WES on eight sporadic or familial patients with “discontinuous cleft” which combined a cleft of the primary and the secondary palate with preservation of part of the intermaxillary palate. Three causative mutations were found in genes previously implicated in human CLP phenotype and/or syndrome. Our work illustrates how well-defined phenotype combined with the power of high throughput technologies significantly contribute to the understanding of genetic factor underlying CLP, and how it could help more accurate clinical, epidemiological, and fundamental research, ultimately resulting in better diagnosis and care of CLP patients(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201