Familial Oculoauriculovertebral Spectrum: A Genomic Investigation of Autosomal Dominant Inheritance.

Objective: Oculoauriculovertebral spectrum (OAVS) encompasses abnormalities on derivatives from the first and second pharyngeal arches including macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular, and vertebral anomalies. We present genetic findings on a 3-generation family affected with macrostomia, preauricular tags and ptosis following an autosomal dominant pattern.

Design: We generated whole-genome sequencing data for the proband, affected father, and unaffected paternal grandmother followed by Sanger sequencing on 23 family members for the top candidate gene mutations. We performed parent and sibling-based transmission disequilibrium tests (TDTs) and burden analysis via a penalized linear mixed model, for segregation and mutation burden, respectively. Next, via bioinformatic tools we predicted protein function, mutation pathogenicity, and pathway enrichment to investigate the biological relevance of mutations identified.

Results: Rare missense mutations in SIX1, KDR/VEGFR2, and PDGFRA showed the best segregation with the OAVS phenotypes in this family. When considering any of the 3 OAVS phenotypes as an outcome, SIX1 had the strongest associations in parent-TDTs and sib-TDTs (P = 0.025, P = 0.052) (unadjusted P-values). Burden analysis identified SIX1 (RC = 0.87) and PDGFRA (RC = 0.98) strongly associated with OAVS severity. Using phenotype-specific outcomes, sib-TDTs identified SIX1 with uni- or bilateral ptosis (P = 0.049) and ear tags (P = 0.01), and PDGFRA and KDR/VEGFR2 with ear tags (both P < 0.01).

Conclusion: SIX1, PDGFRA, and KDR/VEGFR2 are strongly associated to OAVS phenotypes. SIX1 has been previously associated with OAVS ear malformations and is co-expressed with EYA1 during ear development. Efforts to strengthen the genotype-phenotype co-relation underlying the OAVS are key to discover etiology, family counseling, and prevention.