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We report on an 8‐year‐old girl with severe developmental and epileptic encephalopathy due to the compound heterozygous null variants p.(Gln661*) and p.(Leu830Profs*2) in GRIN2A resulting in a knockout of the human GluN2A subunit of the N‐methyl‐D‐aspartate receptor. Both parents had less severe GRIN2A‐related phenotypes and were heterozygous carriers of the respective null variant. Functional investigations of both variants suggested a loss‐of‐function effect. This is the first description of an autosomal recessive, biallelic type of GRIN2A‐related disorder. Nonetheless, there are marked parallels to two previously published families with severe epileptic encephalopathy due to homozygous null variants in GRIN1 as well as various knockout animal models. Compared to heterozygous null variants, biallelic knockout of either GluN1 or GluN2A is associated with markedly more severe phenotypes in both humans and mice. Furthermore, recent findings enable a potential precision medicine approach targeting GRIN‐related disorders due to null variants. [ABSTRACT FROM AUTHOR]

Purpose: Sodium channel gene aberrations are associated with a wide range of seizure disorders, particularly Dravet syndrome. They usually consist of missense or truncating gene mutations or deletions. Duplications involving multiple genes encoding for different sodium channels are not widely known. This article summarizes the clinical, radiologic, and genetic features of patients with 2q24 duplication involving the sodium channel gene cluster. Methods: A systematic review of the literature and report of two cases. Key Findings: Nine individuals with 2q24 duplication involving the sodium channel gene cluster are described (seven female, two male). All presented with severe seizures refractory to anticonvulsant drugs. Seizure onset was in the neonatal period in eight patients with SCN1A-involvement, in infancy in one patient with SCN2A and SCN3A, but no SCN1A involvement. Seizure activity decreased and eventually stopped at 5-20 months of age. Seizures recurred at the age of 3 years in the patient with SCN2A and SCN3A, but no SCN1A involvement. Eight patients had a poor neurodevelopmental outcome despite seizure freedom. Significance: This article describes a distinct seizure disorder associated with a duplication of the sodium gene cluster on 2q24 described in otherwise healthy neonates and infants with severe, anticonvulsant refractory seizures and poor developmental outcome despite seizure freedom occurring at the age of 5-20 months. [ABSTRACT FROM AUTHOR]