A number sign (#) is used with this entry because of evidence that CEBALID syndrome, which comprises craniofacial defects, dysmorphic ears, structural brain abnormalities, expressive language delay, and impaired intellectual development, is caused by heterozygous mutation in the MN1 gene (156100) on chromosome 22q12.

CEBALID 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 dysmorphic ears often associated with conductive or sensorineural deafness. Affected individuals have delayed walking and significant expressive speech and language delay, but many can attend special schools. Brain imaging shows crowding of the posterior fossa, including rhombencephalosynapsis (partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres), as well as perisylvian polymicrogyria and cerebellar hypoplasia/dysplasia (summary by Mak et al., 2020).

See also Gomez-Lopez-Hernandez syndrome (GLHS; 601853), which has an overlapping phenotype.

Mak et al. (2020) reported 22 patients with CEBALID syndrome. All were unrelated, except for 2 brothers (patients 5 and 6). The patients were ascertained due to global developmental delay with mildly delayed walking, hypotonia, feeding difficulties, variably impaired intellectual development, and significant speech delay, particularly affecting expressive language. At least 8 patients were nonverbal. There was a distinctive facial gestalt consistent with abnormal craniofacial development. Most patients had skull shape abnormalities, such as brachycephaly, plagiocephaly, turricephaly, dolichocephaly, and bitemporal narrowing; 3 had craniosynostosis. Other common features included frontal bossing, midface hypoplasia, hypertelorism, downslanting palpebral fissures, short upturned nose, high-arched palate, and mild exorbitism consistent with shallow orbits. All had significant ear anomalies, including small, low-set, posteriorly rotated, and dysplastic ears. Many had recurrent otitis media, and 16 had conductive and/or sensorineural hearing impairment. Six patients had single or rare seizures. Less common features observed in a minority of patients included thin lips, micro/retrognathia, prognathia, crowded teeth, strabismus, nystagmus, optic nerve defects, Duane anomaly (3 patients), scoliosis, inguinal hernia, and congenital diaphragmatic hernia (2 patients). Brain imaging, performed in 17 patients, showed variable abnormalities in all but 2 patients. The most significant findings were rhombencephalosynapsis (8 patients) and perisylvian polymicrogyria (9 patients). Detailed descriptions indicated cerebellar hypoplasia/dysplasia, crowding of the posterior fossa, thickened rostral corpus callosum, prominent posterior clinoid process, and, less commonly, enlarged ventricles or hypoplasia of the olfactory bulbs. Seven patients had a persistent medial primitive trigeminal artery, which the authors noted could have surgical implications. Patient 21 had previously been reported by Tully et al. (2012) and Ishak et al. (2012) as part of larger cohorts of patients ascertained for rhombencephalosynapsis.

Miyake et al. (2020) reported 3 unrelated patients, 2 of Japanese origin and 1 of French descent, with CEBALID syndrome. The patients, who were 6, 5, and 18 years of age, respectively, had severe global developmental delay with severe speech impairment. Developmental quotient was 31 in 1 patient and 18 in another; 1 patient was noted to be nonverbal. The patients had strikingly similar craniofacial abnormalities, including dolichocephaly or platystencephaly, prominent forehead, flat face, midface hypoplasia, bitemporal narrowing, narrow maxilla and mandible, thick eyebrows, widely spaced eyes, low-set or posteriorly rotated ears, depressed nasal bridge with short nose and anteverted nares, and high-arched palate. Two had hypotonia, 1 had recurrent otitis media with conductive and sensorineural hearing loss, and 2 had feeding difficulties; all had hyperphagia. Brain imaging showed polymicrogyria in 2 patients and cerebellar vermis dysplasia in 1; brain imaging was normal in 1 patient at age 6 years.

Clinical Variability

Mak et al. (2020) also reported 5 unrelated patients (patients 24-28) with a milder form of CEBALID syndrome. These patients carried de novo heterozygous frameshift or nonsense mutations in the N-terminal region of the MN1 gene or whole-gene deletions, suggesting MN1 haploinsufficiency. They had milder dysmorphic facies than the first group, conductive hearing loss, and expressive language delay. Brain imaging, performed in 3 of these patients, was normal in 2 and showed platybasia in 1; none had rhombencephalosynapsis.

The majority of heterozygous mutations in the MN1 gene that were identified in patients with CEBALID syndrome by Mak et al. (2020) occurred de novo. However, there was 1 family in which 2 affected brothers inherited the mutation from a mildly affected father who was somatic mosaic for the mutation.

In 22 probands with CEBALID syndrome, Mak et al. (2020) identified germline de novo heterozygous nonsense or frameshift mutations in the MN1 gene (see, e.g., 156100.0001; 156100.0003-156100.0005). In addition, 2 affected sibs (patients 5 and 6) inherited a heterozygous nonsense mutation (Q1273X; 156100.0002) from their mildly affected father (patient 7), who was somatic mosaic for the mutation. The patients, ascertained for syndromic intellectual disability or developmental disorders, underwent whole-exome, whole-genome, or Sanger sequencing from 15 independent research or diagnostic laboratories. The first group of variants, which accounted for most of the mutations, occurred in the C terminus, at the end of exon 1 or in exon 2, and all were predicted to escape nonsense-mediated mRNA decay. This was confirmed by RNA analysis of fibroblasts derived from 3 of these patients (patient 2, 10, and 21), which showed expression of the mutant transcripts at levels similar to wildtype, indicating escape of nonsense-mediated mRNA decay. Although additional functional studies were not performed, Mak et al. (2020) postulated that a truncated protein is produced in these patients, which may have a dominant-negative or gain-of-function effect. In contrast, 3 patients (patients 24, 25, and 26) had nonsense or frameshift mutations in the N-terminal third of the protein, which were predicted to result in nonsense-mediated mRNA decay, and 2 further patients (patients 27 and 28) had de novo heterozygous deletions of the whole MN1 gene found by array analysis. The mutations or deletions in this second group of patients were predicted to cause MN1 haploinsufficiency, and the phenotype was somewhat different than that observed in the first group of patients.

In 3 unrelated patients with CEBALID syndrome, Miyake et al. (2020) identified de novo heterozygous frameshift or nonsense mutations in the C-terminal region of the MN1 gene (R1295X, 156100.0003; Q1279X, 156100.0006; and c.3846_3849del, 156100.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the Exome Variant Server, ExAC, or gnomAD databases, or in an in-house database of 575 controls. In vitro functional expression studies in HeLa cells showed that mutant MN1 formed larger and more insoluble aggregates compared to wildtype. The mutant proteins were more stable and resistant to ubiquitin-proteasome degradation compared to wildtype, suggesting that the C terminus is required for degradation. The mutant proteins, which maintained transactivation activity, also showed a trend towards stronger inhibition of cell proliferation compared to wildtype, which would be consistent with a gain-of-function effect. The deletion of the C terminus would likely increase the fraction of intrinsically disordered regions (IDRs) and possibly alter phase separation. Immunoprecipitation studies showed that the R1295X mutant protein had impaired interaction with ZBTB24 (614064) and no binding to RING1 (602045) or E2F7 (612046) compared to wildtype, although it showed binding to certain partners that wildtype MN1 did not, including MEIS1 (601739) and PBX2 (176311). Transcriptome analysis of lymphoblastoid cells derived from the patient with the R1295X mutation showed both up- and downregulation of genes compared to wildtype, suggesting dysregulated transcription of MN1 target genes.