Partial MEF2C deletion in a Cypriot patient with severe intellectual disability and a jugular fossa malformation: Review of the literature

Abstract

Deletions or intragenic mutations involving the MEF2C gene on chromosome 5q14.3 have generally been associated with a relatively uniform phenotype characterized by severe developmental delay, absent speech, stereotypies, absent or limited gait abilities, lack of a typical facial gestalt and scarcity of major malformations. We report on a patient of Cypriot descent with a de novo, approximately 147 kb in size, partial MEF2C deletion removing exons 1 to 3. He had a history of severe intellectual disability with absent speech, poor eye contact, hand stereotypies and a wide-based gait. A broad-based, shallow jugular pit with an overlying vascular malformation was also present. Partial MEF2C deletions have only been reported in a very small number of patients and have on occasion been associated with relatively milder phenotypes. We present a patient of Cypriot descent with such a deletion and review previously published literature on partial MEF2C gene deletions postulating a key role of the first few exons in the pathogenesis of the disease.

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.…”

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

“…Predictions about how a CNV impacts gene function have long been understood to be important with genes such as DMD, where an in-frame versus out-of-frame CNV means the difference between Becker and Duchenne muscular dystrophy. 95 Similar genotype-phenotype correlations are beginning to be explored and have been proposed for genes including NRXN1, 96,97 AUTS2, 98 MEF2C, 99 and CAMTA1. 100 These correlations are mainly based on clinical observations, but model organism data 98 and examination of transcriptional products from CNV carriers 100 provide some additional support.…”

The association of severe encephalopathy and question mark ear is highly suggestive of loss of MEF2C function

“…9 A suprasternal anomaly, such as a jugular pit or a patch of atrophic and/or reddish skin, has been reported in 6 patients carrying a heterozygous 5q14.3 deletion encompassing all or part of MEF2C. 10,11 There are no discriminating facial features associated with MEF2C haploinsufficiency although bilateral QMEs occur in 1 female patient harboring a 5q14 deletion of~3 Mb and encompassing MEF2C (case 1 in Reference 7 and Figure 1A). Interestingly, case 1 in Reference 7 also presented a suprasternal pit ( Figure 1A).…”