Familial Oculoauriculovertebral Spectrum: A Genomic Investigation of Autosomal Dominant Inheritance

Area of Science:

• Genetics
• Developmental Biology
• Medical Genomics

Background:

• Oculoauriculovertebral spectrum (OAVS) is a complex congenital disorder affecting craniofacial structures derived from the first and second pharyngeal arches.
• OAVS phenotypes include macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular, and vertebral anomalies, often presenting with autosomal dominant inheritance patterns.

Purpose of the Study:

• To investigate the genetic underpinnings of OAVS in a 3-generation family exhibiting macrostomia, preauricular tags, and ptosis.
• To identify specific gene mutations and their correlation with OAVS phenotypes within the affected family.

Main Methods:

• Whole-genome sequencing was performed on the proband and affected father, followed by Sanger sequencing for validation in 23 family members.
• Transmission disequilibrium tests (TDTs) and burden analysis were employed to assess gene segregation and mutation impact on OAVS severity.
• Bioinformatic tools were utilized for predicting protein function, mutation pathogenicity, and pathway enrichment.

Main Results:

• Rare missense mutations in SIX1, KDR/VEGFR2, and PDGFRA demonstrated strong segregation with OAVS phenotypes in the family.
• SIX1 showed the most significant association with OAVS in parent-TDTs and sib-TDTs (P=0.025, P=0.052).
• Burden analysis linked SIX1 and PDGFRA to OAVS severity, while SIX1, PDGFRA, and KDR/VEGFR2 were associated with specific phenotypes like ptosis and ear tags.

Conclusions:

• SIX1, PDGFRA, and KDR/VEGFR2 are significantly associated with OAVS phenotypes.
• SIX1's role in OAVS, particularly ear malformations, is supported by its co-expression with EYA1 during ear development.
• Further research to strengthen genotype-phenotype correlations is crucial for understanding OAVS etiology, genetic counseling, and prevention strategies.