PT - JOURNAL ARTICLE AU - Mirta Basha AU - Bénédicte Demeer AU - Nicole Revencu AU - Raphael Helaers AU - Stephanie Theys AU - Sami Bou Saba AU - Odile Boute AU - Bernard Devauchelle AU - Geneviève Francois AU - Bénédicte Bayet AU - Miikka Vikkula TI - Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes AID - 10.1136/jmedgenet-2017-105110 DP - 2018 Mar 02 TA - Journal of Medical Genetics PG - jmedgenet-2017-105110 4099 - http://jmg.bmj.com/content/early/2018/03/02/jmedgenet-2017-105110.short 4100 - http://jmg.bmj.com/content/early/2018/03/02/jmedgenet-2017-105110.full AB - Background Oral clefts, that is, clefts of the lip and/or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of ~1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance. Genome-wide association studies have identified approximately 30 risk loci for nsCL/P, which could explain a small fraction of heritability.Methods To identify variants causing nsCL/P, we conducted whole exome sequencing on 84 individuals with nsCL/P, drawn from multiplex families (n=46).Results We identified rare damaging variants in four genes known to be mutated in syCL/P: TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their CL/P.Conclusion These data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of ‘missing heritability’ for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers.