Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency

•Exome sequencing for two siblings with suspected congenital disorder of glycosylation reveals mutations in GFM1.•A novel GFM1 variant deep in intron 6 activates a cryptic splice site.•Mutations lead to decreased GFM1 protein levels and disrupted assembly of OXPHOS complexes in fibroblasts.•Clinical course improved at 7 years of age in one of the siblings.

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.