A founder mutation in the ETHE1 gene and ethylmalonic encephalopathy in the Omani population

Abstract

Background: Ethylmalonic encephalopathy (EE) is a devastating early-onset inborn error of metabolism, and heterogenous disorders manifest as chronic diarrhea, petechial rash, and neurological manifestations. The mutation in the ETHE1 gene leads to hydrogen sulfide accumulation and eventually results in mucosal cell damage in the large intestines and vascular endothelial cells system. Case presentation: Here, we describe four patients from three different tribes in Oman, and the clinical data revealed that the four patients shared an early-onset phenotype and the neurological manifestations were variable. The biochemical markers, specifically the urine organic acid and hyperlactimic acidosis, supported and tailored the diagnosis. Molecular diagnosis was confirmed by full gene sequencing of the ETHE1 gene in the index case and followed by target variant testing for others. Interestingly, all four patients identified to harbor the same homozygous missense pathogenic variant (c.487c > t) in the ETHE1 gene, and their parents were all heterozygous. These findings indicate that we probably have a founder variant associated with EE in our area. Conclusion: These findings are of great importance for diagnosis and surveillance for Omani families with EE. Given the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost-effective tool for molecular diagnosis. Additionally, these findings should help in designing appropriate measures for carrier screening measures at the regional level.