Whole Exome Sequencing Identifies Damaging Variants in Indonesians with Clefts

Objectives The interaction between genomics, genetic and environmental factors have been implicated in non-syndromic orofacial cleft development. In the current study, we investigated the contributions of rare and novel genetic variants in known cleft genes using whole exome sequencing (WES) data of Indonesians with non-syndromic orofacial clefts. Design WES was conducted on 6 individuals. Variants in their exons were called and annotated. These variants were filtered for novelty and rarity using MAF of 0 and 1%. Setting Hospital in Indonesia. Patients/Participants Indonesians with non-syndromic orofacial clefts. Interventions Deleterious variants were prioritized. Pathogenic amino acid changes effect on protein structure and function were identified using HOPE. Main Outcome Measure(s) Rare and novel variants in known cleft genes were filtered and their deleteriousness were predicted using polyphen, SIFT and CADD. Results We identified rare (MAF <1%) deleterious variants in 4 craniofacial genes namely MMACHC (rs371937044, MAF = 0.00011). SOS1 (rs190222208, MAF = 0.00045), TULP4 (rs199583035, MAF = 0.067), and MTHFD1L (rs143492706, MAF = 0.0044). MMACHC has a mouse knockout model with facial cleft and failure of palatal fusion. The individual with variant in MMACHC presented with nsCPO. Conclusions Our study provides additional evidence for the role of TULP4, SOS1, MTHFD1L and MMACHC genes in nsOFC development. This is the first time MMACHC is implicated in nsOFC development in humans.