A novel variant in MFN2 linked to a lethal disorder of neonatal onset

Pathogenic variants in the mitochondrial fusion protein Mitofusin2 typically cause axonal Charcot-Marie- Tooth disease type 2A (CMT2A), a progressively degenerative peripheral neuropathy. Here, we present two siblings with a lethal disorder of neonatal onset who carried a novel homozygous MFN2 variant R334K. Given the severe clinical presentation, which is atypical of MFN2 variants, further functional investigations were warranted to confirm the pathogenicity of the R334K variant, which was deemed to be likely pathogenic. Characterization of patient fibroblasts showed severe disruptions all MFN2-related functions that were assayed, including reduced mitochondrial respiration, altered mito-ER contacts, decreased mtDNA copy number and size, as well as increased abundance of cellular lipid droplets. We also observed reduced Complex I activity, which is noted in cells lacking MFN2, but is not standard for pathogenic MFN2 variants that cause CMT2A. These functional deficits, combined with the fact that loss of MFN2 is lethal in model organisms (e.g. mice/fruit-flies), support the notion that the MFN2 R334K is a loss of function variant that is responsible for patient phenotype. Thus, we present a novel pathogenic MFN2 variant causing severe fatal neonatal disease.