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This summary reviews the evidence linking MOXD1 (HGNC:21063) to autosomal dominant nocturnal frontal lobe epilepsy (MONDO_0020300). In a trio-based study of an Italian family, a single variant was identified that co-segregated with the disease phenotype, providing modest but consistent genetic evidence (PMID:36231847).
The clinical validity is currently classified as Limited. The association is supported by data from one family where the variant appears in affected members, though the number of unrelated probands remains low (PMID:36231847). This single-family observation limits broad clinical application without further corroborative studies.
Genetic evidence is based on an autosomal dominant inheritance pattern. The reported variant, c.827T>G (p.Trp276Gly), was observed in the affected family members. Although the variant has been classified as a variant of uncertain significance under ACMG guidelines, its segregation with the phenotype provides initial support that requires additional validation (PMID:36231847).
Functional assessment using in silico structural modeling predicted that the p.Trp276Gly substitution results in loss of critical hydrophilic bonds and expansion of a protein cavity, suggesting a destabilizing effect on the protein structure. This experimental evidence offers supplementary biological plausibility linking MOXD1 dysfunction to ADSHE; however, its reliance on a single study tempers its overall impact (PMID:36231847).
No significant conflicting evidence has been reported, although the limitation to a single family and the VUS status of the variant necessitate caution. Additional families carrying MOXD1 alterations and further functional studies in relevant models would enhance confidence in this gene–disease relationship.
In summary, while the combined genetic and experimental data support a potential role for MOXD1 in autosomal dominant nocturnal frontal lobe epilepsy, current evidence remains limited. Clinicians should consider this association as preliminary, with the key take‑home message being that further studies are required to solidify the clinical utility of MOXD1 in the diagnostic work-up for ADSHE.
Gene–Disease AssociationLimitedOne family with the c.827T>G (p.Trp276Gly) variant co-segregating with ADSHE supports the association; however, the low number of unrelated probands limits broader clinical validity (PMID:36231847). Genetic EvidenceLimitedThe autosomal dominant inheritance pattern and single reported variant in affected individuals provide preliminary genetic evidence, but additional families and variant types are needed (PMID:36231847). Functional EvidenceLimitedIn silico modeling suggests that the p.Trp276Gly variant has a destabilizing effect on the protein, supporting its potential pathogenicity; however, this data comes from a single study (PMID:36231847). |