Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations.

Lin Wan,Xinting Liu,Huimin Chen,Linyan Hu,Guang Yang,Zhi Lin,Zhenfang Wang,Liping Zou,Yulin Sun,Zhichao Li

doi:10.3389/fped.2021.664449

Abstract

Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS.Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases.Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms.Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.

Highlights

Myocyte enhancer factor 2C (MEF2C) haploinsufficiency syndrome (MCHS) has been attributed to 5q14.3 microdeletions (MIM# 613443, developmental delay, stereotypic movements, epilepsy and/or cerebral malformations) [1] and was defined as any microdeletions of chromosome 5q14.3-5q15 that involved multiple genes
Seven patients with confirmed MEF2C mutations who had developmental delay, stereotypic movements or epilepsy were enrolled from the First Medical Center of PLA General Hospital, Fujian Provincial Hospital, and Children’s Hospital of Shanxi
On reviewing previous studies as well as our cohort, we found an interesting phenomenon: patients with intragenic deletions seemed more likely to be ambulatory than the patients with point mutations in MEF2C (6/7 vs. 9/23)

Summary

Introduction

Myocyte enhancer factor 2C (MEF2C) haploinsufficiency syndrome (MCHS) has been attributed to 5q14.3 microdeletions (MIM# 613443, developmental delay, stereotypic movements, epilepsy and/or cerebral malformations) [1] and was defined as any microdeletions of chromosome 5q14.3-5q15 that involved multiple genes (www.omim.org). 23 patients have been reported to have pathogenic and likely pathogenic MEF2C variants or microdeletions without an involvement of other contiguous or distant genes [1, 6,7,8,9,10,11,12,13,14]. We have described a new cohort of seven patients with MEF2C point mutations, discussed their clinical features and reported six novel mutations as well as reviewed previous data of patients having pathogenic or likely pathogenic MEF2C variants or MEF2C microdeletions without the involvement of other contiguous or distant genes, which facilitated us to further clarify MCHS genotypes and phenotypes

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