Agradecimentos: This study would not be possible without the dedication of the patients and families and our colleagues from BDCA participant centers. The authors would like to thank the following BDCA participant centers, which provided samples from patients included in this study: Centro de atenção aos defeitos da face (CADEFI), Faculdade de Medicina de São José do Rio Preto (FAMERP), Centrinho Prefeito Luiz Gomes-Joinville, Universidade Federal do Rio Grande do Norte (UFRN), and Hospital de Clínicas de Porto Alegre. We are also indebted to Gabriela Roldão Correia-Costa for her technical support. This study was partially supported by the National Council for Scientific and Technological Development (CNPq) (#408504/2018-8 and #309782/2020-1), São Paulo Research Foundation (FAPESP #2018 / 21370-4) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES #001), and by the Fonds de la Recherche Scientifique - FNRS Grant J.0228.20 (to MV). The authors thank the Genomics Platform of University of Louvain for the access to the Next Generation Sequencing data analyses cluster. Eleonore Pairet is a Research Fellow (ASP) grantee of the Fonds de la Recherche Scientifique – FNRS. We also thank the National Lottery, Belgium and the Foundation Against Cancer (2010-101), Belgium for their support to the Genomics Platform of University of Louvain and de Duve Institute, as well as the Fonds de la Recherche Scientifique - FNRS Eguipment Grant U.N035.17 for the «Big data analysis cluster for NGS at UCLouvain». Ver menos

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 Ver menos