Novel MYT1 variants expose the complexity of oculo‐auriculo‐vertebral spectrum genetic mechanisms

Abstract

Oculo‐auriculo‐vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis‐regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.

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

“…Overexpression of mutated forms in cellular experiments confirmed their loss-of-function effect and interestingly linked MYT1 to retinoic acid pathway, a known toxic agent in utero , leading to OAVS features on exposed newborns. Other patients with OAVS were then reported carrying MYT1 mutations, although explaining the onset of OAVS in a small percentage of patients14 25 53 (table 3).…”

OTX2duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

“…Epigenetic dysregulation is also regularly suggested to contribute to OAVS 3 8–11. Concerning genetic causes, the first gene associated with OAVS was MYT1 12 13 through five unrelated individuals reported in three different studies 13–15. Recently, Timberlake et al reported SF3B2 as the most frequent gene involved in OAVS 16.…”

Exploration of Novel Genetic Evidence and Clinical Significance Into Hemifacial Microsomia Pathogenesis

“…7 MYT1, a gene known to regulate retinoic acid signaling and central nervous development, 8,9 has been established further causality to HFM spectrum by recurrent clinical reports on unrelated patients with mutations in this gene, 10 and on a deleterious single nucleotide variant and an enrichment of copy number variation (CNV) on its neighboring topologically associating domain. 11 A sporadically reported nonsense variant in ZYG11B was also found causative with regulating role in cell proliferation and retinoic acid pathway, and its homolog zyg11b in zebrafish with crucial role in head cartilage formation. 12 Although EYA3 is the second recurrent gene whose missense variant had been screened out in HFM spectrum patients, transient knockdown of EYA3 in zebrafish altered craniofacial cartilage architecture.…”