Research Centre for Medical Genetics
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MRNA Analysis Revealed a New Pathogenic Variant in the EIF2S3 Gene Leading to MEHMO Syndrome

MEHMO syndrome is a rare type of X-adhesive mental retardation, accompanied by epileptic seizures, hypogenitalism, microcephaly and obesity (OMIM 300148). The disease is sporadic, with a prevalence of less than 1 per million newborns. The literature describes fewer than thirty patients with this syndrome.

The family applied to the Research Centre for Medical Genetics to receive a genetic consultation. In the background check, it turns out that the proband has a cousin with similar pathology. The peculiarities of the clinical picture allowed the geneticists of RCMG to suspect in the proband and his cousin MEHMO syndrome.

Pathogenic variants in the EIF2S3 gene cause MEHMO syndrome as well known. The EIF2S3 gene has twelve protein-coding exons. The optimal DNA diagnostic tool to find pathogenic variants in the EIF2S3 gene is Sanger sequencing of all encoding exons. Most DNA diagnoses of MEHMO syndrome are performed with exomic sequencing. However, since MEHMO syndrome is a rare disease, RCMG developed no DNA diagnosis system. The EIF2S3 gene has a relatively high level of expression in the blood, so it was decided to analyze its mRNA in the functional genomics laboratory.

As a result, a previously undescribed missense option of NM_001415.3 was discovered: c.820C>G; p.(Leu274Val) in both hemizygous cousins. We found the same option in heterozygous female family members.

It has been previously shown that pathogenic variants in the EIF2S3 gene result in chronic activation of the integrated stress response (ISR). Increased DDIT3 gene expression is the marker of that process. This gene encodes a transcription factor that stops the cell cycle and triggers apoptosis in response to cell stress. Therefore, the expression of the gene DDIT3 was analyzed to study the pathogenicity of the found missense variant c.820C>G. That one was significantly higher in the patient than in the control.

The comprehensive analysis enabled the evaluation of the found variant as likely-pathogenic and to carry out complete medical genetic counselling of the requesting family.

Nadezda Ivanova, Victoria Serzhanova, Nina Demina, Darya Guseva, Mikhail Skoblov. mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome. European Journal of Medical Genetics. Volume 65, Issue 2, 2022, 104421, ISSN 1769-7212. (Q3, IF- 2.708)