Severe mental retardation, seizures, and hypotonia due to deletions of MEF2C

Abstract

We present four patients, in whom we identified overlapping deletions in 5q14.3 involving MEF2C using a clinical oligonucleotide array comparative genomic hybridization (CGH) chromosomal microarray analysis (CMA). In case 1, CMA revealed an approximately 140 kb deletion encompassing the first three exons of MEF2C in a 3-year-old patient with severe psychomotor retardation, periodic tremor, and an abnormal motor pattern with mirror movement of the upper limbs observed during infancy, hypotonia, abnormal EEG, epilepsy, absence of speech, autistic behavior, bruxism, and mild dysmorphic features. MRI of the brain showed mild thinning of the corpus callosum and delay of white matter myelination in the occipital lobes. In case 2, an approximately 1.8 Mb deletion of TMEM161B and MEF2C was found in a child with severe developmental delay, hypotonia, and seizures. Patient 3 had epilepsy, hypotonia, thinning of the corpus callosum, and developmental delay associated with a de novo approximately 2.4 Mb deletion in 5q14.3 including MEF2C and five other genes. In case 4, a de novo approximately 5.7 Mb deletion of MEF2C and five other genes was found in a child with truncal hypotonia, intractable seizures, profound developmental delay, and shortening of the corpus callosum on brain MRI. These deletions further support that haploinsufficiency of MEF2C is responsible for severe mental retardation, seizures, and hypotonia. Our results, in combination with previous reports, imply that exon-targeted oligo array CGH, which is more efficient in identifying exonic copy number variants, should improve the detection of clinically significant deletions and duplications over arrays with probes spaced evenly throughout the genome.

5q14.3 neurocutaneous syndrome: A novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C

“…Since 2009, six authors have reported on 5q14.3q15 microdeletions and the associated clinical findings [Cardoso et al, 2009;Engels et al, 2009;Le Meur et al, 2010;Nowakowska et al, 2010;Novara et al, 2010;Zweier et al, 2010]. From these reports, a common syndrome of developmental delay/mental retardation, hypotonia, absent speech, mild facial dysmorphology, seizures, and brain anomalies emerges.…”

“…This phenotype has been described in six reports encompassing 19 patients with a 5q14.3q15 microdeletion ( Fig. 1) [Cardoso et al, 2009;Engels et al, 2009;Le Meur et al, 2010;Novara et al, 2010;Nowakowska et al, 2010;Zweier et al, 2010]. An emerging consensus points to haploinsufficiency of MEF2C, a member of the myocyte enhancer factor-2 (MEF2) transcription factor family [Potthoff et al, 2007], as the genetic etiology underlying this complex phenotype.…”

“…Indeed, 3 of the 19 patients lack deletion of MEF2C, as seen in Figure 1, so MEF2C's role in the 5q14.3q15 microdeletion phenotype was not self-evident. MEF2C's causative role was buttressed with the identification of two affected patients whose microdeletions only involved MEF2C [Novara et al, 2010;Nowakowska et al, 2010] and another patient who had a nonsense mutation of MEF2C in lieu of a 5q14.3q15 deletion [Le Meur et al, 2010].…”

The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10

“…Mutations in human MEF2C are strongly associated with neuronal disorders, including seizures, mental retardation and epilepsy (Le Meur et al, 2010;Novara et al, 2010;Nowakowska et al, 2010), demonstrating the important role for MEF2C in the development of neuronal lineages in humans. Mutations in human SOX10 often cause a severe form of Waardenburg syndrome (Type IV, also known as Waardenburg-Hirschsprung disease), which involves aganglionic colon and severe pigmentation defects (Parisi and Kapur, 2000;Pingault et al, 1998;Pingault et al, 2010).…”

The Transcription Factor Neural Retina Leucine Zipper (NRL) Controls Photoreceptor-specific Expression of Myocyte Enhancer Factor Mef2c from an Alternative Promoter

“…MEF2C activity is modulated by post-translational modifications in response to cytoplasmic signals including calcium (37). Mutations in human MEF2C are associated with neurological disorders including mental retardation and seizures (43,44).…”