The MEF2C gene (MIM * 600662), located on chromosome 5, belongs to the myocyte enhancer factor-2 (MEF2) family of transcription factors. It contains up to 11 coding exons spanning approximately 100kb of genomic DNA.
MEF2C protein plays a pivotal role in cardiac and skeletal muscle development, blood vessel morphogenesis, neural crest and craniofacial development, and neurogenesis (Dong et al. 2017).
Variants causing MEF2C haploinsufficiency syndrome
- Thirty-eight 5q14.3 microdeletions, including 13 partial deletions of the MEF2C gene and 25 complete deletions, have been reported in the literature so far.
- Interestingly, 6 deletions that do not encompass the MEF2C gene (5’ or 3’ upstream) have also been reported and associated with the same clinical presentation. Functional studies were not performed but positional effect may be the explanation (Engels et al. 2009, Cardoso et al. 2009, Sobreira et al. 2009, Shimojima et al. 2012, Boutry-Kryza et al. 2015).
- Eleven mutations, including 7 truncating variants and 4 missense variants, have been reported in the literature so far. No recurrent mutations have been described. The team of Anita Rauch (Zurich, Germany) performed functional studies in two patients with missense variants and showed that MEF2C transcriptional activity was consistently abolished.
The pathophysiologic mechanism is haploinsufficiency or low ME2FC protein expression in patients’ cells. Aberrations in the exon 2 (MADS/MEF2 and transcriptional activation domains) may have a key role in the pathogenesis of the disease (Tanteles et al. 2014).
Correlation genotype-phenotype
Clinical variability may be partially explained by the molecular aspect.
Hemangiomas are frequently reported in patients with MEF2C haploinsufficiency syndrome. In individuals with 5q14.3 microdeletion, it has been explained by the contiguous gene deletion involving the adjacent RASA1 gene. Indeed, haploinsufficiency of this gene is causative for capillary malformation – arteriovenous malformation syndrome (MIM# 608354). However, two patients with an intragenic MEF2C deletion of the exons 1 to 3 had multiple hemangiomas as well. As MEF2C has been shown to play an important role in vessel development, point mutations in the first exons of MEF2C may cause vascular malformations (Vrecar et al. 2017).
5q14.3 duplications
Only five patients with 5q14.3 duplications, ranging from 4.6Mb to 5.5Mb, have been reported in the literature. These duplications share a common region of about 3.3Mb, involving the entire MEF2C gene. None intragenic duplication has been reported so far.
The pathophysiologic mechanism is different and may be high MEF2C protein expression in patients’ cells.
Diagnostic testing
Rett-like phenotype is associated with pathogenic variants in numerous genes, including FOXG1, CDKL5, SLC9A6, TCF4, ZEB2, IQSEC2, STXBP1, CNTNAP2, BPAN and this list is still growing.
Micro-array analysis is the best first-line genetic testing for intellectual disability syndrome.
Then, ID gene panel could be requested if microarray shows a normal result.