Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum

Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.