Investigation of genetic causes in oculoauriculovertebral spectrum etiology

Oculo-Auriculo-Vertebral Spectrum (OAVS) is a genetically and phenotypically heterogeneous disorder which occurs due to a developmental defect in the first and second pharyngeal arches. In this study, 23 OAVS patients with diverse clinical findings were studied to identify the genetic etiology of this disorder. Patients were screened for copy number variations using the Affymetrix CytoScan Optima array Kit and also screened for MYT1 mutations using BigDye terminator on an ABI Prism 3500 genetic analyzer. Furthermore, two patients underwent WES analysis. Using these approaches, three CNVs (one deletion, two duplications) were found in chromosomes 8, 15, 16. The clinical relevance of the copy number variations is discussed within the framework of incomplete penetrance and monoallelic expression. In addition, the deletion on the 8th chromosome was thought to be associated with clinical findings by altering the genome architecture. In addition, a de novo unbalanced translocation; between X and 4th chromosomes was found in one of the patients and was considered pathogenic. No causative mutation was found in MYT1 gene. WES analysis revealed a novel heterozygous nonsense mutation in EFTUD2; responsible for Mandibulofacial Dysostosis with Microcephaly that has common clinical findings with OAVS. In the other patient who underwent WES analysis a novel heterozygous missense mutation was identified in RNF213, which was previously suspected as a candidate gene for OAVS. Duplication of 16p13.11 region, aneuploidies of X chromosome and EFTUD2 mutations were previously implicated in OAVS molecular etiology. This study provides further genetic heterogeneity to this disorder, confirming the importance of microarray-based studies and whole exome sequencing analysis in patients with a complex phenotypic disorder such as OAVS. Keywords: OAVS, microarray, 16p13.11, EFTUD2, RNF213