SRPX2 was first reported in relation to epilepsy (primarily characterized as Rolandic epilepsy-speech dyspraxia syndrome but changed to epilepsy by the ClinGen Epilepsy GCEP, in 2021) in 2006 when 2 multiplex families were described in a single paper (PMID:16497722). This remained the sole SRPX2 gene-disease relationship report until 2017 (PMID:28440294). Overall, three missense variants have been reported in humans to date (with one additional variant reported through a mouse model (PMID:24179158)). However, these variants do not have supportive functional evidence. SRPX2 is not constrained for missense variants and at least one of the variants is present at a high frequency in the general population. While initial evidence (such as segregation and initial experiments) seemed to support pathogenicity in respect to epilepsy, subsequent evidence including mean allele frequency in gnomAD, a high dN/dS ratio, variable clinical presentations and the detection of another putative cause in one of the families (GRIN2A) (PMID:23933820) brings this gene disease relationship into question. Without significant supportive genetic evidence, a correlation to epilepsy and/or neurodevelopmental disorders is not supported.
This gene-disease pair was originally evaluated by the ClinGen Epilepsy GCEP on July 8, 2018. It was reevaluated in October 2023. As a result of this reevaluation, the classification was changed from disputed to refuted due to lack of any additional supportive evidence. This updated classification was approved by the ClinGen Epilepsy GCEP on October 17th, 2023.
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).
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