MAGI2 was evaluated for evidence supporting and refuting its relationship with autosomal dominant epilepsy. Of note, variation in MAGI2 has also been described in association with autosomal recessive nephrotic syndrome. Evidence for this gene-disease relationship is not considered here.
MAGI2 was initially thought to be involved in epilepsy after large deletions including MAGI2 (and other genes) were reported in individuals with infantile epilepsy (PMIDs: 18565486, 26030165). MAGI2 was thought to be the causative gene because it has been found to interact with stargazin, a protein that has been associated with epilepsy in mice (PMID: 16870733), and it was the region with the most overlap amongst patients with documented infantile spasms (PMID: 18565486). There have been reports of individuals with deletions at the 7q11.23-7q2.11 locus, where MAGI2 is located. One individual has a deletion at this locus that spans part of MAGI2, but this individual does not have a diagnosis of epilepsy (PMID:18565486). There are also reports of four other individuals with deletions in this region that do not include MAGI2, but who have been diagnosed with infantile spasms, suggesting that there is an alternate cause of disease (PMIDs: 21694734, 14636357, 20146355). While some MAGI2 single nucleotide variants have recently been reported in individuals with epilepsy, the genetic testing method used in the paper does not sufficiently rule out other genetic causes of epilepsy, and many variants are present with high allele counts in gnomAD (PMID: 30986657).
Furthermore, when considering experimental evidence, MAGI2 null mouse models have not been reported to present with epilepsy (PMIDs: 25108225, 27932480). Instead, these mice have renal abnormalities consistent with the phenotypic presentation of patients with biallelic intragenic null frameshift variants. This suggests that the absence of MAGI2 may cause nephrotic syndrome, rather than epilepsy.
In summary, the evidence supporting the relationship between MAGI2 and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on October 17, 2023.
This gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on June 19, 2018 and was classified as disputed. In September 2021 and July 2023, it underwent minor administrative updates, but evidence was not reevaluated. Evidence was reevaluated on October 17, 2023. As a result of this reevaluation, the classification did change from disputed to refuted due to a continued lack of valid supporting evidence, and the exclusion of all other new evidence (PMIDs: 25497044, 30986657).
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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