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KIF13A (HGNC:14566) has emerged as a novel susceptibility locus for progressive supranuclear palsy (MONDO_0019037). Two independent whole‐genome sequencing studies using large European cohorts have identified significant association signals implicating KIF13A in PSP (PMID:39152475) and (PMID:38234807). These studies included 1,718 PSP cases each, and although the analyses were based on case‑control association without detailed within‐family segregation, the reproducibility across studies lends robust statistical support to this association.
The genetic evidence is further exemplified by the reported variant c.2357dup (p.Asn786LysfsTer18) found in KIF13A. While this frameshift variant was originally described in a functional study of a neuroectodermal syndrome (distinct from PSP), its inclusion here underscores the impact that loss‑of‑function events in KIF13A can have. In the context of PSP, such a variant represents the potential for deleterious alleles to influence disease risk despite the absence of classical Mendelian inheritance.
In terms of inheritance mode, the association with PSP appears to be complex rather than fitting a simple autosomal dominant or recessive pattern. The risk conferred by KIF13A is best interpreted within a multifactorial framework, where genetic predisposition interacts with other risk factors to contribute to disease pathogenesis.
Direct functional evidence linking KIF13A to PSP remains limited. No studies to date have shown functional disruption of KIF13A in cellular or animal models specifically recapitulating progressive supranuclear palsy phenotypes. However, preliminary experimental insights suggest that KIF13A may be involved in intracellular trafficking processes relevant to tau protein aggregation, a key hallmark of PSP pathology.
No conflicting evidence has been reported that specifically refutes the association between KIF13A and PSP. While additional segregation studies and mechanistic experiments are warranted to further validate this association, the convergent findings across two large genome‐wide analyses provide a compelling genetic basis for further exploration.
In conclusion, the integration of robust genetic association data from two independent studies, supported by the potential mechanistic relevance of loss‑of‑function variants in KIF13A, establishes a moderate level of evidence for its involvement in progressive supranuclear palsy. This association supports diagnostic decision‑making and commercially relevant genetic panels, and it lays the groundwork for future functional studies to refine therapeutic strategies.
Gene–Disease AssociationModerateTwo independent whole‐genome sequencing studies in large cohorts (1,718 PSP cases each [PMID:39152475] and [PMID:38234807]) provided consistent association signals, despite the absence of detailed familial segregation data. Genetic EvidenceModerateStatistical associations across two sizable case‐control cohorts and the demonstration of a representative loss‑of‑function variant support a moderate level of genetic evidence for KIF13A in PSP. Functional EvidenceLimitedDirect functional studies in PSP models are lacking; preliminary data from related cellular processes suggest potential mechanistic relevance, but further experimental validation is needed. |