Preprint reports novel MGME1 variant causing mitochondrial DNA depletion syndrome in South Indian families

Mitochondrial DNA (mtDNA) maintenance disorders are a genetically heterogeneous group of inherited conditions arising from defects in the replication or repair of the mitochondrial genome. Mitochondrial genome maintenance exonuclease 1 (MGME1) is a nuclear-encoded nuclease required for mtDNA replication and genome stability; biallelic pathogenic variants in MGME1 are a recognised cause of mitochondrial DNA depletion syndrome 11 (MTDPS11), characterised by proximal myopathy, ophthalmoplegia, and multisystem involvement.

A preprint posted to bioRxiv reports a novel homozygous MGME1 missense variant — c.820G>A (p.Ala274Thr) — identified through sequencing of five affected individuals from unrelated South Indian families. Affected individuals presented with proximal myopathy (muscle weakness affecting limb girdle), chronic progressive external ophthalmoplegia (progressive weakness of the muscles controlling eye movement), and evidence of broader mitochondrial dysfunction. The variant was not identified in a heterozygous or homozygous state at appreciable frequency in publicly available population databases, supporting its likely pathogenicity in this context.

The report extends the mutational and population spectrum of MGME1-related disease and adds to a growing literature documenting mitochondrial disorders in South Asian patient cohorts that have historically been underrepresented in genomic databases. As a preprint, these findings have not yet undergone peer review.