Work

Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association

Year: 2026

Type: article

Abstract: Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease. • mtDNA variants previously reported were not detected using standard filters. • Low-level variants were only observed when removing quality filters. • Similar frequencies were found in ALS and non-ALS subjects. • Variants were mapped to homopolymeric regions prone to sequencing errors. • These findings suggest sequencing artifacts over disease association.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2026.107412