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The association between STYXL1 and epilepsy has been investigated in families with a consanguineous background, where early evidence suggested that a homozygous missense mutation might contribute to the disease phenotype. In a 2015 case report, a founder missense mutation was identified in a consanguineous Asian family presenting with moderate intellectual disability, epilepsy, and behavioral complexities (PMID:25724587).
Subsequent multi‐patient studies published in 2019 re‐evaluated the same missense variant and noted that the homozygous p.Pro311Ala change, observed in multiple affected siblings across two families, is most likely benign based on additional segregation analyses and international database validations (PMID:30472486).
Genetic evidence supports an autosomal recessive mode of inheritance, with segregation analyses identifying at least 2 additional affected relatives carrying the variant. The reported variant, formatted as c.932C>G (p.Pro311Ala), was observed in affected individuals; however, its pathogenicity remains in dispute due to conflicting familial studies.
Experimental assessments, including functional assays and additional segregation analyses, have failed to demonstrate a clear deleterious impact on protein function, thereby not supporting a straightforward pathogenic mechanism. This incongruity between the initial report and subsequent studies creates a discordant picture of the gene‐disease association.
In summary, while initial findings sparked interest in STYXL1 as a candidate gene for epilepsy, the weight of current genetic and functional evidence does not robustly support its pathogenicity, rendering the association disputed. Key take‑home: Caution is warranted in clinical interpretation and genetic counselling regarding STYXL1 variants in epilepsy, pending further evidence to resolve these conflicts.
Gene–Disease AssociationDisputedThe initial report from a consanguineous family (PMID:25724587) suggested a founder mutation association, but subsequent segregation analyses and multi‐patient studies have indicated that the p.Pro311Ala variant is most likely benign (PMID:30472486). Genetic EvidenceDisputedWhile a homozygous missense variant was reported in affected individuals, limited genetic evidence overall and additional segregation analyses in separate families refute a clear pathogenic role. Functional EvidenceDisputedFunctional assays and further experimental assessments did not demonstrate a deleterious effect of the STYXL1 variant, undermining its candidacy for pathogenicity. |