MN1

Inheritance Pattern: AD

Disease ID:MONDO:0032908

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0032908

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0032908

Submitter: ClinGen

The *MN1* gene is located on chromosome 22 at 22q12.1 and encodes a transcription cofactor, *MN1* proto-oncogene, transcriptional regulator, which is required during later stages of palate development for growth and medial fusion of the palatal shelves. Two disease entities have been reported in association with this gene: craniofacial defects-dysmorphic ears-brain abnormalities-language delay-intellectual disability (CEBALID) and meningioma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found distinct differences in phenotype and in molecular mechanism. Therefore, the two disease entities have been split into two disease entities for curation. This curation addresses *MN1* in association with CEBALID syndrome. The *MN1* gene was first reported in relation to autosomal dominant CEBALID syndrome in 2020 (Miyake et al. 2020, PMID: 31839203; Mak et al. 2020, PMID: 31834374). CEBALID syndrome, previously known as *MN1* C-terminal truncation syndrome, is a complex developmental disorder characterized by global developmental delay, variably impaired intellectual development, and craniofacial and structural brain abnormalities. Common features include abnormal skull shape, characteristic facial features with midface hypoplasia, hypertelorism, and high-arched palate, and low-set, posteriorly rotated dysplastic ears often associated with conductive or sensorineural deafness. Brain imaging typically shows rhombencephalosynapsis, perisylvian polymicrogyria and cerebellar hypoplasia/dysplasia. At least 10 individuals with CEBALID syndrome were identified with 10 unique variants (nonsense, frameshift, whole gene deletion) in the *MN1* gene were scored in this curation (PMIDs: 31839203, 31834374, 33351141, 33351070, 37575653). More evidence is available in the literature, however the maximum score for genetic evidence (12 points) has been reached (PMIDs: 31834374, 34708882, 36124717). Most of the variants occurred de novo and are located in the C-terminal region of the gene that is predicted to escape NMD. Several loss-of-function variants in the N-terminal region that are expected to undergo NMD were also reported with milder phenotypic presentations. The mechanism of pathogenicity is unclear; however, it is suggested that deletion of the C-terminal region enhances *MN1* protein aggregation which leads to disruption of *MN1* target genes. Supporting experimental evidence includes biochemical function, expression data, as well as a mouse model. Mn1 knockout null mice die at or soon after birth with a cleft palate, severe bone abnormalities, with several bones completely absent or hypoplastic (PMID: 15870292). Heterozygous mice had mild defects (hypoplastic membranous bone and incomplete penetrance of the cleft palate) and a normal lifespan. In summary, there is definitive evidence to support the relationship between *MN1* and CEBALID syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 2nd, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0032908

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011789

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0032908

Submitter: G2P