Whole genome sequencing of a family with autosomal dominant features within the oculoauriculovertebral spectrum.

BACKGROUND

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 three-generation family affected with macrostomia, preauricular tags and uni- or bilateral ptosis following an autosomal dominant pattern.

METHODS

We generated whole genome sequencing data for the proband, affected parent and unaffected paternal grandparent followed by Sanger sequencing on 23 family members for the top 10 candidate genes: and We performed parent and sibling-based transmission disequilibrium tests 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 and showed the best segregation with the OAV phenotypes in this family. When considering any of the 3 OAVS phenotypes as an outcome, had the strongest associations in parent-TDTs and sib-TDTs (p=0.025, p=0.052) (unadjusted p-values). Burden analysis identified (RC=0.87) and (RC=0.98) strongly associated with OAVS severity. Using phenotype-specific outcomes, sib-TDTs identified with uni- or bilateral ptosis (p=0.049) and ear tags (p=0.01), and and with ear tags (both p<0.01).

CONCLUSION

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