Preliminary Identification of Causative Gene Mutations in a CL/P Pedigree

Objectives: Cleft lip and/or palate (CL/P) is one of the most common congenital craniofacial defects of complex aetiology. Although several molecular pathways and genes have been implicated in the pathogenesis of CL/P, the more common non-syndromic (NS) CL/P do not have idetified mutations. This study set out to identify the potential causative gene mutation in a pedigree with left CL/P for further evaluation.
Methods: Exome sequencing was applied for three members of an extended family, including the proband with left CLP, the affected aunt with left cleft lip and the unaffected father.
Results: Exome sequencing generated 11.26Mb of aligned base reads on average, of which 97.4% reached ≥20X coverage. A total of >73,000 mutation variants on average were obtained. 329 sequence variants were included because of presence in both patients and absence from the unaffected. All known variants (the Exome Variant Server or the 1000 Genome browser at a minor allele frequency >0.05) and non-deleterious SNVs (determined by SIFT and PolyPhen2) were excluded. We also examined previously reported genes in CL/P for sequence variants and did not identify any pathogenic alterations. By using Phenolyzer and searching for information regarding each gene from PubMed, we obtained three genes that were susceptible (listed below).
Conclusions: Exome sequencing was performed to identify the causative mutations in a NSCL/P pedigree. In our analysis, we seleted three candidate genes. Further experiments are needed to verify their roles in the pathogenesis of CL/P.