Comparative analysis of clinical phenotypes and genetic characteristics in MEF2C-associated neurodevelopmental
Xin Li1, Jia-Jun Ma1, Lin-Xue Meng1
1Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing City 400014, China; National Clinical Research Center for Child Health and Disorders, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, China.
Background:
Myocyte enhancer factor 2C (MEF2C) is among the important genes associated with neurodevelopmental disorders (NDDs). The phenotypic distinctions between MEF2C pathogenic variants and 5q14.3 microdeletions remain unclear.
Methods:
We retrospectively collected the information of patients from our centre between May 2019 and October 2024 and identified them as having MEF2C mutations by whole-exome sequencing (WES). We searched the literature related to MEF2C mutations and 5q14.3 microdeletions and summarized the clinical features and genetic characteristics of the patients.
Results:
Five patients with MEF2C mutations were identified from our hospital, and 34 articles were selected for analysis. Data from 62 MEF2C-associated copy number variations (CNVs) and 42 MEF2C mutations were analysed. We found that regression was more common in the mutation group (21.6 %, 8/37) than in the CNV group (2.0 %, 1/51; P = 0.008). Patients with mutations in MEF2C were more likely to present with a history of febrile seizures (45.2 % vs. 25.8 %, P = 0.040) and autistic traits (91.9 % vs. 74.5 %, P = 0.037). Myoclonic seizures (29.4 % vs. 70.6 %, P = 0.025), infantile epileptic spasm syndrome (3.3 % vs. 31.8 %, P = 0.018), refractory epilepsy (11.1 % vs. 47.8 %, P = 0.012), diffuse epileptiform discharges from electroencephalograms (15.0 % vs. 42.9 %, P = 0.2) and abnormal corpus callosum (23.1 % vs. 55.9, P = 0.06) may occur more often in the CNV group.
Conclusion:
Patients with CNVs presented a higher prevalence of refractory epilepsy and vascular malformations, whereas those with point mutations more frequently presented with developmental regression, febrile seizure history and autistic traits. These genotype-phenotype correlations could inform genetic testing strategies.
Insights
Myocyte enhancer factor 2C (MEF2C) pathogenic variants and 5q14.3 microdeletions cause neurodevelopmental disorders. Point mutations are linked to developmental regression and autistic traits, while copy number variations (CNVs) are associated with refractory epilepsy.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Myocyte enhancer factor 2C (MEF2C) is a key gene implicated in neurodevelopmental disorders (NDDs).
- The precise phenotypic differences between MEF2C pathogenic variants and 5q14.3 microdeletions are not fully understood.
- Understanding these distinctions is crucial for accurate diagnosis and management of NDDs.
Purpose of the Study:
- To delineate the distinct clinical and genetic features of MEF2C pathogenic variants compared to 5q14.3 microdeletions.
- To identify genotype-phenotype correlations for MEF2C-related neurodevelopmental disorders.
- To inform genetic testing strategies and improve patient care.
Main Methods:
- Retrospective analysis of patients with MEF2C mutations identified via whole-exome sequencing (WES) at a single center.
- Comprehensive literature review of MEF2C mutations and 5q14.3 microdeletions.
- Comparative analysis of clinical features and genetic characteristics between mutation and copy number variation (CNV) groups.
Main Results:
- Developmental regression was significantly more common in patients with MEF2C mutations (21.6%) compared to CNVs (2.0%).
- MEF2C mutations were associated with a higher incidence of febrile seizures (45.2%) and autistic traits (91.9%).
- CNV group showed higher rates of myoclonic seizures, infantile epileptic spasm syndrome, and refractory epilepsy.
Conclusions:
- MEF2C CNVs are linked to a higher prevalence of refractory epilepsy and vascular malformations.
- MEF2C point mutations are more frequently associated with developmental regression, febrile seizures, and autistic traits.
- Established genotype-phenotype correlations can guide genetic testing and diagnostic approaches for NDDs.
