MYT1 – Oculo-Auriculo-Vertebral Spectrum (Craniofacial Microsomia)

Oculo-auriculo-vertebral spectrum, also termed Craniofacial Microsomia, is an autosomal dominant disorder characterized by variable hemifacial hypoplasia, microtia, mandibular hypoplasia, ocular defects, and vertebral anomalies. MYT1, encoding the myelin transcription factor 1, was first implicated as the causative gene via whole-exome sequencing in two sporadic cases harboring de novo truncating and missense variants (two probands) (PMID:27358179).

Subsequent studies have identified one additional de novo c.323C>T (p.Ser108Leu) variant in a Brazilian cohort (PMID:28612832), two novel variants in two unrelated individuals from a 128-trio study (PMID:32871052), and a recurrent SNV in five unrelated patients (PMID:33880880), bringing the total to ten unrelated probands.

The allelic spectrum comprises five distinct missense changes (p.Ser108Leu, p.Ser105Leu, p.Gly927Glu, p.Pro78Thr and the recurrent SNV) and one truncating allele (p.Arg9Ter). The exemplar variant c.323C>T (p.Ser108Leu) disrupts the repression of retinoic acid receptor genes, confirming its functional impact (PMID:28612832).

Inheritance is autosomal dominant, with de novo occurrence documented in multiple probands; no extended familial segregation has yet been reported.

Functional assays demonstrate that morpholino knockdown of zebrafish myt1a produces craniofacial cartilage defects mirroring human phenotypes (PMID:27358179), and cell culture overexpression shows that wild-type MYT1 downregulates RARA, RARB, and RARG, a function abrogated by pathogenic variants (PMID:27358179; PMID:28612832).

Collectively, multiple unrelated cases, consistent autosomal dominant de novo inheritance, and concordant functional disruption of retinoic acid signaling support a Strong gene–disease association for MYT1 in craniofacial microsomia. MYT1 should be included in diagnostic panels for OAVS to guide clinical decision-making.

References

• Journal of medical genetics • 2016 • Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS. PMID:27358179
• European journal of human genetics • 2017 • A novel de novo mutation in MYT1, the unique OAVS gene identified so far. PMID:28612832
• Molecular genetics & genomic medicine • 2020 • MYT1 role in the microtia-craniofacial microsomia spectrum. PMID:32871052
• American journal of medical genetics. Part A • 2021 • Novel MYT1 variants expose the complexity of oculo-auriculo-vertebral spectrum genetic mechanisms. PMID:33880880

Evidence Based Scoring (AI generated)