Novel MEF2C point mutations in Chinese patients with Rett (−like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation

Abstract

BackgroundMEF2C (Myocyte-specific enhancer factor 2C) has been associated with neurodevelopmental disorders. This study aimed at delineating the clinical profiles of MEF2C gene mutations.MethodsIn total, 112 Chinese patients with intellectual disability (ID) were recruited, including 44 patients presented with Rett syndrome (RTT) or RTT-like syndrome, and 68 patients with non-syndromic ID. Targeted next-generation sequencing (NGS) was performed. Detailed clinical information was collected.ResultsFive heterozygous MEF2C gene mutations were identified, of which three were novel. The MEF2C mutant rate was 4.5% (5/112) in total, and 6.8% (3/44) in the RTT (−like) cohort. All patients with MEF2C gene mutation presented with cognitive impairment, gross motor delay, speech disorder and autistic features. Four patients had epilepsy, which responded well to antiepileptic drugs. One female was diagnosed with classical RTT, two females with RTT-like syndrome, and two males with non-syndromic ID. Generally, the phenotype of two males with relatively downstream mutations (c.565C > T, p.Arg 189*; c.766C > T, p.Arg 256*) was milder than that of three females with upstream mutations (c.48C > G, p.Asn16Lys; c.334G > T, p.Glu112* and c.403-1G > T).ConclusionsOur findings expanded the current understanding of the consequences of MEF2C dysfunctions, especially MEF2C point mutations. MEF2C mutations are associated with a broad clinical spectrum, ranged from classical RTT to non-syndromic ID. Through our study, it can be inferred that there is correlation between the phenotype and MEF2C-genotype, the mutation site. Overall, the MEF2C gene mutational analysis should be performed in ID cohort, especially in patients with features overlapped with RTT.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0699-1) contains supplementary material, which is available to authorized users.

MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review

“…Autonomic features such as cutaneous pallor and hypopnea with cyanosis were also reported in our case. Data from previously reported patients also reinforce the broad spectrum of seizure types observed in MEF2C-related epilepsy, with febrile seizures being most common [1][2][3][4][5][6][7][8][9][10]. Along with the variability of seizure types are the EEG changes, with different epileptiform and non-epileptiform abnormalities.…”

“…Ten publications including 22 patients were selected (Table 1). [1][2][3][4][5][6][7][8][9][10] Out of these 23 patients (including the child in this report) harbouring MEF2C pathogenic, likely pathogenic variants, or microdeletions encompassing exclusively the MEF2C gene, 19 have had seizures (82%). Seizures were reported in the first 12 months of life in 12 of the 19 patients (63%).…”

“…2 The phenotype may resemble Rett's syndrome in some cases, with stereotypic behaviour, particularly hand flapping, but no microcephaly or neuroregression [3]. To the best of our knowledge, only 22 cases of MEF2C pathogenic and likely pathogenic variants or microdeletions without involvement of other contiguous or distant genes have been reported [1][2][3][4][5][6][7][8][9][10]. So far, the electroclinical patterns in MEF2C haploinsufficiency have been infrequently and inconsistently described.…”

Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges

“…Now, with the possibility of multiplexing genes and patients, sequencing them at the same time, the cost-efficiency of the technique is comparable to the Sanger sequencing analysis of a single gene [13]. Therefore, the global implementation of these technologies in research laboratories has led to an important increase in the identification of diseases or genes related to RTT/RTT-like phenotype that in some cases had previously been associated with other well-described diseases [14,15,16]. While the added value of NGS diagnostics in all of these patients is clear, an optimal implementation strategy for diagnostic laboratories is yet to be established [17].…”

Anxiolytic and Anxiogenic? How the Transcription Factor MEF2 Might Explain the Manifold Behavioral Effects of Oxytocin

“…Those oxytocin-induced cellular effects can depend on MEF2 expression levels as the transcription factor is known to be a regulator of metaplasticity, i.e., it determines how neurons respond to stimuli by shifting plasticity thresholds (54). Moreover, mutated MEF2 has been associated with Rett-like syndrome (62,63) and autism spectrum disorder (64)(65)(66). Recent publications indicate a connection between dysregulated synapse number, i.e., hyperconnectivity, and symptoms of autism spectrum disorder (67); moreover, lower plasma oxytocin levels have been reported in children with autism and social impairments (68,69).…”