Developmental and Epileptic Encephalopathy via the GRIN2B Gene

GRIN2B-related developmental and epileptic encephalopathy 27 (DEE27) is a rare disorder with an age of onset ranging from infancy to 9 years. Major clinical features (documented in >50% of cases) include severe global developmental delay, severe intellectual disability, and seizures of various types. Minor features of GRIN2B-related disease (<50% of cases) include mild to moderate ID, microcephaly, spasticity, autistic behaviors, and hypotonia. MRI may reveal structural brain malformations in some patients, but the phenotype is highly variable (Platzer et al. 2017. PubMed ID: 28377535).

A diagnosis of DEE27 can provide prognostic and family planning information. This disorder often results in profound disability and reduced life expectancy (Platzer et al. 2017. PubMed ID: 28377535). Treatment typically includes supportive care and management of symptoms. In one individual, dietary supplementation of L-serine was believed to benefit neurological function (Soto et al. 2019. PubMed ID: 31213567).

GRIN2B-related developmental and epileptic encephalopathy is autosomal dominant and apparently fully penetrant—to date nearly all cases have involved de novo variants. Nearly all molecular variant types have been associated with GRIN2B-related disease. Pathogenic missense variants are the most frequently reported. They are enriched in the agonist binding domains (S1 and S2) and pore forming transmembrane domains (M1-4). These regions are depleted of natural missense variation in the general population (Karczewski et al. 2020. PubMed ID: 32461654; Swanger et al. 2016. PubMed ID: 27839871; Hu et al. 2016. PubMed ID: 27818011). Pathogenic missense variants have been shown to affect several biophysical properties including, agonist binding, channel gating, and receptor biogenesis. What’s surprising is that variants predicted to result in loss- or gain-of receptor function appear to cause similar neurological phenotypes (Swanger et al. 2016. PubMed ID: 27839871). Predicted null variants (nonsense, frameshifts, and large deletions) are believed to cause disease by haploinsufficiency (Endele et al. 2010. PubMed ID: 20890276; Lemke. 2014. PubMed ID: 24272827; Hu et al. 2016. PubMed ID: 27818011), and GRIN2B is intolerant to chain-terminating variants (Genome Aggregation Database; Karczewski et al. 2020. PubMed ID: 32461654).

GRIN2B(GluN2B)-knockout mice die shortly after birth. Hippocampal neurons in these animals have impaired long term depression, among other phenotypes (Kutsuwada et al. 1996. PubMed ID: 8789948). Therefore, this gene is believed to be essential for the development and function of the mammalian nervous system.

GRIN2B encodes the alpha-2B subunit of N-methyl-D-aspartate NMDA receptors. These ligand-gated ion channels bind glutamate and glycine and serve as important detectors of activity for synaptic plasticity, learning, and memory. NMDA receptors are heterotetrameric, composed of one alpha-1 subunit and one or more alpha-2 A, B, C, or D subunit. This composition is dependent on developmental timing (Endele et al. 2010. PubMed ID: 20890276).

The clinical sensitivity of this test alone is expected to be low (<1%).  GRIN2B-related developmental and epileptic encephalopathy is an ultra-rare disorder with approximately 100 disease-associated variants reported to date. In addition, there are approximately one hundred genes associated with similar epileptic encephalopathy phenotypes. However, since the great majority of pathogenic variants in GRIN2B involve single base pair substitutions, the analytical sensitivity of this test is predicted to be very high (>99%).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the GRIN2B gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.