ESPE Abstracts (2015) 84 P-3-903

Genotype and Phenotype Characterisation in Two Patients with MEHMO Syndrome

Juraj Staníka,b, Martina Škopkováa, Daniela Staníkováa,b, Jozef Ukropeca, Daniel Daniša, Timea Kurdiováa, Barbara Ukropcováa, Lubica Ticháb, Iwar Klimeša & Daniela Gašperíkováa

aDIABGENE & Diabetes Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia; bFirst Department of Pediatrics, Medical Faculty at Comenius University, Bratislava, Russia

Background: MEHMO (microcephaly, epilepsy, hypogenitalism, mental retardation, obesity) is a rare disorder with X-linked inheritance. Only three families with this disorder were described previously, with the linkage to a region on X chromosome. No specific gene has been identified so far.

Aims and objectives: The aim was to identify the genetic etiology in two unrelated Slovak male probands (4.5 and 1.5 years old respectively) with the clinical diagnosis of MEHMO and describe the genotype-phenotype correlation.

Methods: Blood samples of both probands and their parents were obtained. DNA analysis by the whole exome sequencing (WES) approach was performed. Subsequent analyses of identified variants were focused on the chromosome X. Candidate sequence variants were verified by direct sequencing by Sanger.

Results: Analysis of exome in proband 1 has identified 18 variants on chromosome X. Haplotype analysis showed that only three of them were found also in the mother and the mother’s mother of the proband 1, and only one variant – in the gene EIF2S3 – was located in the previously described region of the chromosome X associated with MEHMO. The variant is a frame-shift mutation with premature stop codon influencing eight last amino acids of the protein. The same mutation was found also in the proband 2 and his mother. The phenotype of the probands had several common features, i.e. microcephaly, mental retardation, epilepsy, growth retardation, obesity, and diabetes. Nevertheless, the phenotype was more severe in the older proband 1 including panhypopituitarism and frequent respiratory infections.

Conclusion: This is the first identification of a gene (EIF2S3) causing MEHMO syndrome. EIF2S3 encodes the γ subunit of the eukaryotic translation initiation factor 2 (eIF2), which is involved in protein synthesis. Point mutations in this gene have been previously identified in several families with microcephaly and impaired intellect (i.e. milder phenotype than MEHMO).

Funding: This work was supported by the Slovak Research and Development Agency (APVV 0187-12).