Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS)

Abstract

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

“…Methylation studies were performed in 41 OAVS individuals, compared with controls, revealing moderate epigenetic variations. More stochastic epigenetic variants were identified in patients with OAVS, but without any recurrence 126. More studies are needed to improve the knowledge of such epigenetic events that could explain how genes interact with environmental factors to impair branchial arches development.…”

Copy number variation analysis implicates novel pathways in patients with oculo‐auriculo‐vertebral‐spectrum and congenital heart defects

“…Additional evidence supporting a role of epigenetic defects in OAVS is the observation of BAPX1 allelic imbalance in patients' fibroblasts, which can be rescued by treating cells with histone deacetylase inhibitors 17 . Moreover, a moderate epigenetic variation in genes implicated in basic chromatin dynamics were recently recognized in OAVS by genome‐wide DNA methylation analysis 18 . Among other non‐genetic causes of OAVS, gestational diabetes, vascular disruption, and exposure to teratogenic agents including thalidomide, primidone, or retinoic acid have been reported 1 …”

“…17 Moreover, a moderate epigenetic variation in genes implicated in basic chromatin dynamics were recently recognized in OAVS by genome-wide DNA methylation analysis. 18 Among other non-genetic causes of OAVS, gestational diabetes, vascular disruption, and exposure to teratogenic agents including thalidomide, primidone, or retinoic acid have been reported. 1 The prevalence of CHDs in OAVS ranges from 5% to 58%, 19 with septal and conotruncal defects occurring more commonly.…”

Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism

“…Stochastic Epigenetic Mutations (SEMs) and regions enriched in SEMs were identified as previously described by our group [10,15,[17][18][19].…”