GRIN2B – West syndrome

Using targeted epilepsy gene panel screening of 357 patients, de novo heterozygous GRIN2B variants were identified in two individuals presenting with West syndrome and severe developmental delay (PMID:24272827). No other family members were affected, supporting de novo occurrence.

Both individuals harboured missense variants clustering within the NR2B ion channel re‐entrant loop: c.1844A>T (p.Asn615Ile) ([PMID:24272827]). A subsequent screen of 47 unexplained infantile spasms cases did not yield additional de novo mutations but detected an inherited GRIN2B splice‐site alteration (c.2011-5_2011-4delTC) of uncertain significance.

Functional assessment in Xenopus laevis oocytes demonstrated that p.Asn615Ile and the related p.Val618Gly variant markedly reduced the Mg2+ block and increased Ca2+ permeability, resulting in a profound gain-of-function effect. This biophysical alteration correlates with severe epileptic phenotypes in West syndrome and underscores facilitated NMDA receptor activity in epileptogenesis ([PMID:24272827]).

These in vitro assays provide moderate experimental evidence linking GRIN2B gain-of-function mutations to West syndrome pathogenesis, consistent with facilitated NMDA receptor signaling driving early infantile spasms.

Overall, the convergence of two de novo variants in unrelated probands and concordant functional data supports a Moderate gene–disease association. GRIN2B should be included in diagnostic gene panels for West syndrome and related early-onset epileptic encephalopathies.

Key Take-home: De novo gain-of-function GRIN2B variants are an established cause of West syndrome, warranting their consideration in clinical testing and potential targeted therapy.

References

• Annals of neurology • 2014 • GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. PMID:24272827

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