The Enigmatic Etiology of Oculo-Auriculo-Vertebral Spectrum (OAVS): An Exploratory Gene Variant Interaction Approach in Candidate Genes

The clinical diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. Genetic and non-genetic factors have been associated with microtia/OAVS. Although the etiology remains unknown in most patients, some cases may have an autosomal dominant, autosomal recessive, or multifactorial inheritance. Among the possible genetic factors, gene–gene interactions may play important roles in the etiology of complex diseases, but the literature lacks related reports in OAVS patients. Therefore, we performed a gene–variant interaction analysis within five microtia/OAVS candidate genes (HOXA2, TCOF1, SALL1, EYA1 and TBX1) in 49 unrelated OAVS Mexican patients (25 familial and 24 sporadic cases). A statistically significant intergenic interaction (p-value < 0.001) was identified between variants p.(Pro1099Arg) TCOF1 (rs1136103) and p.(Leu858=) SALL1 (rs1965024). This intergenic interaction may suggest that the products of these genes could participate in pathways related to craniofacial alterations, such as the retinoic acid (RA) pathway. The absence of clearly pathogenic variants in any of the analyzed genes does not support a monogenic etiology for microtia/OAVS involving these genes in our patients. Our findings could suggest that in addition to high-throughput genomic approaches, future gene–gene interaction analyses could contribute to improving our understanding of the etiology of microtia/OAVS.