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!
KCNMB2 (HGNC:6286) has been evaluated in multi‐patient studies for its potential association with hippocampal sclerosis of aging (MONDO_0005544). Although this gene was included in risk genotype panels alongside other genes such as GRN and ABCC9, the available data have not demonstrated a robust association with disease‐specific neuroimaging or cerebrospinal fluid biomarkers (PMID:27003218, PMID:28189700).
In genetic analyses, the risk allele (rs9637454_A) within KCNMB2 was assessed in large cohorts; however, neither brain atrophy measures nor CSF protein levels showed significant correlation with this variant. The lack of a statistically significant association and absence of segregation data across affected family members limit the genetic evidence supporting KCNMB2’s role in hippocampal sclerosis of aging (PMID:27003218, PMID:28189700).
No additional familial studies or case reports have documented multiple unrelated probands with KCNMB2 variants that segregate with the hippocampal sclerosis phenotype. Without replication of these findings or corroborative evidence from independent cohorts, the overall genetic contribution of KCNMB2 remains unconvincing.
Functional evidence for the role of KCNMB2 in hippocampal sclerosis is also limited. Although a KCNMB2 missense variant, c.370G>C (p.Gly124Arg), has been functionally evaluated in the context of autism spectrum disorder (PMID:36203817), similar functional assays in a hippocampal sclerosis model are lacking. Therefore, no clear pathogenic mechanism has been established for HS-Aging.
Integration of the genetic and experimental data indicates that, while KCNMB2 was initially included in analyses of HS-Aging risk genes, the evidence does not support a strong or definitive gene‑disease association for this gene in the context of hippocampal sclerosis of aging. The discrepant findings and absence of supportive segregation and functional data currently constrain the diagnostic utility of KCNMB2 variants for this phenotype.
Key take‑home sentence: Despite its inclusion in risk panels, the current multi-patient and functional assessments do not substantiate a reliable clinical role for KCNMB2 in hippocampal sclerosis of aging, advising caution in its use for diagnostic screening.
Gene–Disease AssociationLimitedMulti‐patient studies did not demonstrate a significant association of the KCNMB2 risk allele (rs9637454_A) with hippocampal sclerosis phenotypes, and no segregation data were reported (PMID:27003218, PMID:28189700). Genetic EvidenceLimitedAnalyses across large cohorts failed to yield statistically significant correlations between KCNMB2 variants and disease‐specific biomarkers, restricting the genetic evidence to observational associations without replication. Functional EvidenceLimitedThere is a lack of functional studies linking KCNMB2 to hippocampal sclerosis of aging; existing functional data pertain to a variant evaluated in autism spectrum disorder, which is not directly applicable to HS-Aging (PMID:36203817). |