Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome

Background MEGDHEL is an autosomal recessive syndrome defined as 3‐MEthylGlutaconic aciduria (3‐MGA) with Deafness, Hepatopathy, Encephalopathy, and Leigh‐like syndrome on magnetic resonance imaging, due to mutations in the SERAC1 (Serine Active Site Containing 1) gene, which plays a role in the mitochondrial cardiolipin metabolism. Methods We report the case of a young patient who presented with a convulsive encephalopathy, 3‐methylglutaconic aciduria, deafness, and bilateral T2 hypersignals of the putamen and the thalami, who passed away at 8 years of age. Results Analysis of nuclear genes using an ampliSeq™ targeted custom panel disclosed two compound heterozygous variants in the SERAC1 gene: a nonsense substitution in exon 4, c.202C>T, resulting in a premature stop codon (p.Arg68*), and a novel variant at a canonical splicing site upstream exon 4 (c.129‐1G>C). mRNAs sequencing from the fibroblasts of the patient showed that the splice site variant resulted in exon 3 skipping without frameshift while Western blot experiments showed the absence of SERAC1 expression compared to controls and abnormal filipin staining. Conclusion We showed that the loss of the putative transmembrane domain of SERAC1, due to a novel splice site variant, impairs the protein expression and is responsible for the MEGDHEL syndrome.