Variants in GRIN2D were first reported in individuals with autosomal dominant global developmental delay and seizures in 2016 (Li et al., PMID: 27616483). Since then, many individuals have been reported with variants in GRIN2D, generally presenting with various seizure types, developmental delays, and muscle tone or movement abnormalities within the first year of life. Individuals frequently present with cerebral atrophy as well. For this reason, the Epilepsy GCEP has decided to curate variants in GRIN2D under the disease term complex neurodevelopmental disorder (MONDO:0100038).
Twelve missense variants that have been reported in 16 probands in 6 publications (PMIDs: 27616483, 30280376, 31504254, 32860008, 33397303, 33482465) are included in this curation. The mechanism of pathogenicity appears to be both loss- and gain-of-function (PMIDs: 35228668, 27616483). This gene-disease relationship is also supported by experimental evidence including in vitro functional assays and protein interaction studies (PMIDs: 18779583, 31504254 35228668). Disease-causing variants may show decreased receptor surface expression, either enhanced or reduced sensitivity to agonists, and altered channel open probability. In summary, GRIN2D has a definitive relationship with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the Epilepsy Gene Curation Expert Panel on July 3, 2018. It was re-evaluated on March 15, 2022. As a result of this reevaluation, the classification changed from Limited to Definitive due to publication of additional patients. This curation also underwent an administrative update on January 4, 2023 in which the disease term was changed from developmental and epileptic encephalopathy to a broader term, complex neurodevelopmental disorder. No new evidence has been reviewed or added.
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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