Nonerythrocytic spectrin beta (SPTBN2) was first reported in relation to autosomal dominant spinocerebellar ataxia in 2006 (Ikeda et al., PMID: 16429157). Features of autosomal dominant SPTBN2 related disease include but are not limited to: cerebellar ataxia, nystagmus, developmental delay, and cerebellar atrophy. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in the molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into two disease entities: spinocerebellar ataxia 5 (OMIM:600224), spinocerebellar ataxia recessive 14 (OMIM:615386). The split curation for autosomal recessive SPTBN2 related spinocerebellar ataxia has been curated separately. 16 variants (14 missense and 2 in-frame indels that have been reported in 18 probands in 9 publications (PMIDs: 16429157, 25981959, 22914369, 31617442, 31066025, 31721007, 30898343, 29915382, 33801522) are included in this curation. Segregation in a large well phenotyped family with extensive genotyping yielded approximately 90 affected with consistent features and all affected members genotyped, carried the familial variant (PMID 16429157). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be gain-of-function, though the precise nature of the altered function is unclear. This gene-disease relationship is also supported by an animal model, expression study and functional alteration assay (PMIDs: 9826670, 20603325, 25057192). Expression of a human patient derived variant nearly fully recapitulated the ataxia and cerebellar atrophy features in a mouse model and a cell-culture model in a mouse neuronal cell line (Neuro2a) showed disruption to sub-cellular localization. Further functional evidence was used to weight case-level evidence and suggested that at least one mechanism for disease could be related to an increase in variant SPTBN2 binding affinity for actin (PMID: 37626910). In summary, there is definitive evidence supporting the relationship between SPTBN2 and autosomal dominant spinocerebellar ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date Wednesday Sepetember 10, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.