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

Abstract

BackgroundOculoauriculovertebral Spectrum (OAVS) encompasses a wide variety of anomalies on derivatives from the first and second pharyngeal arches including macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular and vertebral anomalies. We present the genetic findings of a large three-generation family with multiple members affected with macrostomia, preauricular tags and uni- or bilateral ptosis following an autosomal dominant segregation pattern.MethodsWe 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:KCND2, PDGFRA, CASP9, NCOA3, WNT10A, SIX1, MTF1, KDR/VEGFR2, LRRK1, andTRIM2. We performed parent and sibling-based transmission disequilibrium tests and burden analysis to explore segregation and burden of candidate gene mutations. Bioinformatic analyses investigated the biological connection between genes and the abnormal phenotypes.ResultsOverall, rare missense mutations inSIX1, KDR/VEGFR2, andPDGFRAshowed the best evidence of segregation with the OAV phenotypes in this family. When considering affection with any of the 3 OAVS phenotypes as an outcome, parent-TDTs and sib-TDTs (unadjusted p-values) found thatSIX1(p=0.025, p=0.052), followed byPDGFRA(p=0.180, p=0.069) andKDR/VEGFR2(p=0.180, p=0.069) have the strongest associations in this family. Burden analysis via a penalized linear mixed model identifiedSIX1(RC=0.87) andPDGFRA(RC=0.98) as having the strongest association with OAVS severity. Using phenotype-specific ogfrautcomes, sib-TDTs identified associations between (1)SIX1with uni- or bilateral ptosis (p=0.049) and ear tags (p=0.01), (2)PDGFRAandKDR/VEGFR2with ear tags (both p<0.01).ConclusionOur study reports the genomic findings of a large family with multiple individuals affected with OAVS phenotypes with autosomal dominant inheritance. Our findings narrow down to three potential candidate genes,SIX1, PDGFRA, andKDR/VEGFR2. Among these,SIX1has been previously associated with OAVS ear malformations and it is co-expressed withEYA1during ear development. Attempts to strengthen the genotype-phenotype co-relation underlying the OAVS of phenotypes are essential to discover the etiological factors leading to this complex and burdensome condition as well as for family counseling and prevention efforts.