Molecular investigation in Orofacial Clefts with Microphthalmia-Anophthalmia-Coloboma spectrum

Abstract Orofacial clefts (OC) are the most common birth defects in humans and approximately 30% of them form the group of syndromic orofacial clefts (SOCs). Microphthalmia/anophthalmia/coloboma spectrum (MAC) can be associated with OC, however the genetic etiologies of OC-MAC have been poorly characterized. This study describes genomic findings among individuals with OC-MAC recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole exome sequencing (WES) were performed in 17 individuals with OC-MAC. Genotype-phenotype correlation was based on clinical data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them involving the CHD7 gene. Variant of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function. Investigation by WES seems to be the most effective method for diagnosis in OC-MAC. This study also reinforces the genetic heterogeneity of OC-MAC, highlights the presence of the CHD7 gene, and the importance of genes related to ciliopathies in this phenotype.