Background: Pathogenic variants in GRIN2B are predominantly associated with neurodevelopmental disorders (NDDs). However, our understanding of the genotype-phenotype correlations and the optimal treatment strategies is limited.
Methods: We collected clinical data of seven new patients from the Xiangya Hospital and conducted an extensive literature review. Subsequently, we carried out comparisons of clinical features between patients with gain-of-function (GOF) variants and patients with loss-of-function (LOF) variants, as well as patients with LOF missense variants and LOF truncating variants.
Results: We identified seven patients, five of whom had novel variants (p.Phe554Ser, p.Val821Phe, p.Ile641Thr, p.Asn649Ser, and p.Gly1182Arg), and two of whom had known variants (p.Gly820Val and p.Met818Leu). Of the seven cases, 4 (57.14%) presented with epilepsy. Two of these individuals (carrying the p.Ile641Thr and p.Met818Leu variants, respectively) achieved seizure control after receiving memantine. The clinical manifestations included severe developmental delay /intellectual disability (DD/ID) and hypotonia in 100% of cases, as well as microcephaly in 28.57% of cases. Brain imaging results were available for six cases, five of which (83.33%) had abnormal results. Combining our patients (n = 7) and those reported in the literature (n = 98), a total of 105 patients were analyzed. These patients carried 84 pathogenic variants, ten of which were recurrent. The two most frequently occurring variants were p.Gly820Ala and p.Gly689Ser. The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%). We further analyzed the clinical genotypes and phenotypes of 55 patients with LOF variants and 16 patients with GOF variants. Variants located in the transmembrane domain predominantly resulted in a GOF effect. GOF variants were more likely to cause epilepsy and microcephaly than LOF variants. Moreover, in comparison to LOF truncated variants, missense variants were associated with more severe clinical phenotypes, including severe DD/ID, language delay, and movement disorders.
Conclusions: This study reports five novel GRIN2B variants and seven additional patients. Notably, it is the first report to distinguish between GOF and LOF GRIN2B variants, which have distinct clinical phenotypes. Furthermore, memantine has been shown to be effective in controlling seizures and improving cognition.
Keywords: GRIN2B; Gain-of-function; Loss-of-function; Neurodevelopmental disorders; Phenotype-genotype associations.
© 2025. The Author(s).