Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
MTHFSD has been implicated in amyotrophic lateral sclerosis (ALS) based on evidence from a study that screened 43 ALS patients of North-African Jewish origin (PMID:31108397). In that study, 30% of the patients carried at least one homozygous rare in‑silico damaging variant in genes related to ALS pathways. Although MTHFSD was not reported with a specific coding variant, it was noted among genes with altered expression, being downregulated in ALS patient tissues. The genetic evidence for MTHFSD remains limited due to the lack of a directly identified pathogenic variant, absence of segregation data, and no recurrence specifically established for this gene. The inclusion of MTHFSD in both case report and multi‑patient study panels supports its consideration as a candidate, yet these association signals do not reach the level of moderate or strong evidence.
Functional assessment studies for MTHFSD are sparse. No dedicated functional assay, animal model, or rescue experiment has been performed to validate a direct mechanistic role in ALS. The only supporting experimental data involves transcriptomic observations suggesting altered regulation of MTHFSD in ALS patient tissues. Without clear insights into the mechanism of pathogenicity, such as haploinsufficiency or a dominant‑negative effect, the functional evidence remains limited. Further studies including in‑depth functional analyses will be essential to confirm any causative role. Overall, although preliminary, the current findings encourage additional research to potentially enhance diagnostic confidence and inform future therapeutic strategies.
Gene–Disease AssociationLimitedMTHFSD was implicated based on its downregulation in ALS patient tissues from a cohort of 43 patients (PMID:31108397), but no specific pathogenic variant or segregation data have been reported. Genetic EvidenceLimitedThere are no directly reported rare coding variants in MTHFSD, and its association is inferred from its inclusion among genes with altered expression in ALS, thereby limiting the robustness of the genetic evidence. Functional EvidenceLimitedThe functional evidence is primarily based on transcriptomic observations without dedicated in vitro or in vivo functional studies, leaving the mechanistic role of MTHFSD in ALS insufficiently characterized. |