ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23389741 2013 study reporting on 16 patients with neurobehavioral phenotypes, epilepsy, and abnormal movements with MEF2C haploinsufficiency . They include one patient with a novel frameshift mutation (c833delT) in MEF2C, two subjects with deletions of only one gene MEF2C, and 13 subjects with deletions of 5q14.3 containing MEF2C and other adjacent genes. No parental information was reported in this paper.
20513142 Zweier et al. (2010) identified 4 different de novo heterozygous mutations in the MEF2C gene in 362 probands with intellectual disability who were screened for mutations in this gene. Two of the four are truncating variants. A de novo heterozygous MEF2C variant c. 99dupT, p.E34X exon 3 was identified in a 14-year-old boy with intellectual disability, absent speech, hypertonia, seizures onset at age 10 months, mildly enlarged ventricles, and mildly dysmorphic facial features. A de novo heterozygous MEF2C variant c.226_236del11, p.H76fsX15 was identified in a 7-year-old girl with severe intellectual disability, hypotonia, seizure onset at 3-6 months, and dysmorphic facial features.
19592390 Le Meur et al. (2010) identified a de novo heterozygous nonsense mutation (p.S228X) in the MEF2C gene in a girl (case 7) with severe intellectual disability, stereotypic movements, epilepsy, and cerebral malformation. In case 5, a 216 Kb deletion including single gene MEF2C was identified in 8 year old proband presenting a Rett-like phenotype with developmental delay, poor eye contact, epilepsy, stereotypic hand-mouth movements, episodes of hyperventilation and apnea.

Haploinsufficiency phenotype comments:

The MEF2C haploinsufficiency syndrome includes intellectual disability, epilepsy, autism, abnormal movements, brain abnormalities, and some dysmorphic features. Haploinsufficiency of the MEF2C gene appears to be responsible for most of the clinical features seen in 5q14.3 microdeletions. To date, all reported deletions and pathogenic point mutations have been de novo. Additional evidence: -PMID: 23001426. Bienvenu et al. (2013) identified a de novo heterozygous 1-bp deletion (c. 457delA; p.Asn153ThrfsTer33) in exon 5 of the MEF2C gene in an 8-year-old girl with poor feeding, hypotonia, strabismus, delayed motor milestones, myoclonic febrile seizures, microcephaly, and mild dysmorphic features.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There have been cases reported of multigenic duplications at 5q14.3 including MEF2C in individuals with neurodevelopmental disorders, as discussed below. While MEF2C has been proposed as a causative gene in these cases, the effects of the other genes cannot be ruled out. Currently, there have been no reports of isolated MEF2C duplications. -PMID: 23402836. Novara et al. 2013 reported two patients with mild cognitive impairment and microcephaly who had non-focal duplications including MEF2C. One other MEF2C non-focal duplication reported in a previous publication was also reviewed. The common duplicated RefSeq genes are: TMEM161B, LINC00461, MEF2C, CETN3, MBLAC2, POLR3G, GPR98, ARRDC3 and LOC100129716. Data showed that the expression of MEF2C and CETN3 mRNA was statistically higher in patients compared to controls. The role played by MEF2C in central nervous system and craniofacial development strongly suggests that duplication of this gene is responsible for the probands' phenotypes . -PMID: 26864752 Cesaretti et al. 2016 descirbed a 5p14.3 duplication identified prenatally in a monochorionic twin pregnancy with corpus callosum abnormalities. In this case, the duplicated region included three genes associated with well?defined pathologies, RASA1 (CM-AVM), MEF2C, and GPR98 (Usher syndrome type 2C). Thus, among the genes included in the duplicated region identified in our cases, MEF2C seems to be the only one to take part in central nervous system development, particularly in neural crest and craniofacial development and in neurogenesis. In the discussion, the authors mentioned that the Italian Database of Troina ( described a smaller duplication (567?Kb) including only MEF2C was detected (id 14740_01573_Troina) in a child affected with severe intellectual disability, generalized hypotonia, and epilepsy. As of February 2020, this website is no longer accessible. -PMID: 31375103 Yauy et al. 2019 reported a "patient with mild intellectual deficiency with a de novo balanced translocation t(3;5). Breakpoints were fully explored by microarray, Array Painting and Sanger sequencing. No gene disruption was found but the chromosome 5 breakpoint was localized 228-kb upstream of the MEF2C gene. The predicted Topologically Associated Domains analysis shows that it contains only the MEF2C gene and a long non-coding RNA LINC01226. RNA studies looking for MEF2C gene expression revealed an overexpression of MEF2C in the lymphoblastoid cell line of the patient."