Characterization of a Familial Goldenhar Syndrome Case Using Whole-Exome Sequencing

TL;DR

This study explores the genetic and epigenetic factors behind Goldenhar syndrome in a Lebanese family using whole-exome sequencing and methylation analysis.

Contribution

The study identifies potential genetic and epigenetic contributors to Goldenhar syndrome in a familial context.

Findings

A shared missense variant in the MID1 gene was found in affected individuals.

A de novo mutation in FBXW11 and a frameshift in NDUFAF8 were linked to craniofacial and cardiac anomalies.

Hypomethylation in ZC3H3 suggests an epigenetic role in disease variability.

Abstract

Background: Goldenhar syndrome (oculo–auriculo–vertebral spectrum, OAVS) is a rare congenital disorder characterized by craniofacial malformations, systemic anomalies, and significant phenotypic variability. Although it is the second most common craniofacial malformation after a cleft palate, the genetic etiology of Goldenhar syndrome remains largely unexplored. This study aimed to identify genetic variants contributing to Goldenhar syndrome in a Lebanese family with three affected individuals, using whole-exome sequencing and complementary genomic approaches. Methods: Whole-exome sequencing was performed on the nuclear family to identify variants associated with the syndrome. Complementary DNA methylation and gene ontology analyses were conducted to explore epigenetic modifications. Results: A missense shared variant in the MID1 between the affected individuals [NP_000372.1): p. Ile593Phe] gene was observed in the family, while current ACMG evidence was insufficient to establish causality. Additional variants were identified, including a de novo mutation in FBXW11 and a rare frameshift alteration in NDUFAF8, with limited segregation, implicating these genes in associated phenotypes such as craniofacial anomalies and cardiac defects. DNA methylation analysis revealed hypomethylation at CpG sites within the ZC3H3 gene, suggesting an epigenetic contribution to disease variability. Conclusions: Our findings underscore the genetic and epigenetic complexity of Goldenhar syndrome, providing new insights into its molecular etiology and highlighting the challenges of variant interpretation in familial cases of rare congenital disorders.

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