MN1 – CEBALID syndrome

MN1 C-terminal truncation (MCTT) syndrome, also known as CEBALID syndrome, is a neurodevelopmental disorder characterized by craniofacial dysmorphism, brain malformations, and intellectual disability. It arises from heterozygous C-terminal truncating variants in the MN1 gene that cluster within the last two exons and lead to gain-of-function effects.

The condition is inherited in an autosomal dominant manner, with all reported variants occurring de novo. To date, 28 unrelated individuals have been described with de novo nonsense or frameshift variants truncating the MN1 C-terminus, including c.3743G>A (p.Trp1248Ter) (PMID:34708882; PMID:37575653; PMID:34975401; PMID:31839203). No instances of inheritance or segregation in multiplex families have been reported.

Affected individuals typically present in early childhood with global developmental delay, characteristic facial dysmorphism, and sensorineural hearing impairment. Additional features may include partial rhombencephalosynapsis, palate anomalies, and variable brain MRI findings, reflecting phenotypic heterogeneity.

Functional studies demonstrate that C-terminal truncations of MN1 increase mutant protein stability, promote nuclear aggregation, and inhibit cell proliferation in vitro, consistent with a dominant gain-of-function mechanism (PMID:31839203; PMID:34975401). Animal models further implicate MN1 in craniofacial development and osteoblast function.

The proposed pathogenic mechanism involves disrupted ubiquitin-mediated proteasomal degradation and dysregulated transcriptional activation by the truncated MN1 protein. These molecular alterations converge on developmental pathways controlling neural and facial morphogenesis.

Collectively, the genetic evidence of multiple de novo truncating variants, concordant functional data, and consistent clinical phenotype support a Strong clinical validity classification for the MN1–CEBALID syndrome association. Genetic testing for MN1 C-terminal variants enables definitive diagnosis and informs multidisciplinary management.

References

• International journal of developmental neuroscience • 2022 • Novel truncating variant of MN1 penultimate exon identified in a Chinese patient with newly recognized MN1 C-terminal truncation syndrome: Case report and literature review. PMID:34708882
• Journal of pediatric genetics • 2023 • A Novel Pathogenic Variant in the MN1 Gene in a Patient Presenting with Rhombencephalosynapsis and Craniofacial Anomalies, Expanding MN1 C-terminal Truncation Syndrome. PMID:37575653
• Frontiers in molecular neuroscience • 2021 • MN1 Neurodevelopmental Disease-Atypical Phenotype Due to a Novel Frameshift Variant in the MN1 Gene. PMID:34975401
• American journal of human genetics • 2020 • Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities. PMID:31839203

Evidence Based Scoring (AI generated)