mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome

• DOI: 10.1016/j.ejmg.2022.104421
• Publication Date: 2022-01-07T02:19:48Z
• Authors: Nadezda Ivanova; Victoria Serzhanova; Nina Demina; Darya Guseva; Mikhail Skoblov
• Keywords: Exome; Microcephaly; Coding region

EIF2S3 pathogenic variants have been shown to cause MEHMO syndrome - a rare X-linked intellectual disability syndrome. In most cases, DNA diagnostics of MEHMO syndrome is performed using exome sequencing. We describe two cousins with profound intellectual disability, severe microcephaly, microgenitalism, hypoglycemia, epileptic seizures, and hypertrichosis, whose clinical symptoms allowed us to suspect MEHMO syndrome. To confirm this diagnosis, we designed an mRNA analysis for the EIF2S3 gene. It is a cost-effective method to detect coding sequence variants in multi-exonic genes, as well as splicing defects and allelic imbalance. Our mRNA sequence analysis revealed a novel EIF2S3 variant c.820C>G in both cousins. We also found the same variant in female family members in the heterozygous state. To investigate the pathogenicity of the c.820C>G variant, we performed expression analysis, which showed that the DDIT3 transcript level was significantly increased in the patient relative to the controls. We, thus, demonstrate that mRNA analysis is an efficient tool for performing genetic testing in patients with distinct phenotypic features.