Developmental and Epileptic Encephalopathy via the GRIN2D Gene

GRIN2D-related developmental and epileptic encephalopathy is a rare disorder which presents within the first year of life.  The first cases described were diagnosed with early infantile epileptic encephalopathy-46 (EIEE46, Li et al. 2016. PubMed ID: 27616483; Tsuchida et al. 2018. PubMed ID: 30280376).  The phenotype was later expanded to include developmental delay and additional neurological features (XiangWei et al. 2019. PubMed ID: 31504254).  Major features (documented in >50% of cases) include severe global developmental delay, intellectual disability, hypotonia, and various, often intractable, seizures.  Minor features of GRIN2D-related disease (<50% of cases) include mild dysmorphic features, autistic behaviors, attention deficit disorder, microcephaly, movement disorders and oculomotor apraxis.  Most patients have normal MRIs, but abnormalities have included loss of white matter volume, dilated ventricles, thin corpus callosum, and cerebral atrophy (XiangWei et al. 2019. PubMed ID: 31504254; Tsuchida et al. 2018. PubMed ID: 30280376; Li et al. 2016. PubMed ID: 27616483; Camp and Yuan. 2020. PubMed ID: 31918992).

A diagnosis of GRIN2D-related developmental and epileptic encephalopathy can provide prognostic information and guide pharmacological therapy.  This disorder results in profound disability and reduced life expectancy (Camp and Yuan. 2020. PubMed ID: 31918992).  Conventional anti-epileptics drugs used in combinations have proven effective in reducing seizure activity in some individuals (i.e. valproate, topiramate, ethylloflazepate, levetiracetam, clonazepam, and oral steroids; Camp and Yuan. 2020. PubMed ID: 31918992). In addition, targeted NMDA suppression has shown some promise- the pore-blocker memantine reduced seizure activity in two of three patients with gain-of-function variants (Li et al. 2016. PubMed ID: 27616483; XiangWei et al. 2019. PubMed ID: 31504254). Finally, early evidence suggests that immunotherapy may be effective in reducing seizure activity (Hausman-Kedem et al. 2020. PubMed ID: 32289570).

GRIN2D-related disease is autosomal dominant and apparently fully penetrant—to date nearly all cases have involved de novo missense variants.

Pathogenic variants in GRIN2D are enriched in three functional protein domains including the pre-M1 helix, M3 transmembrane motif, and carboxyl-terminal domain (XiangWei et al. 2019. PubMed ID: 31504254). The coding sequence is moderately intolerant to missense variation based on data from gnomAD, and the three regions listed above are particularly depleted of natural missense variation (XiangWei et al. 2019. PubMed ID: 31504254). At least one recurrent de novo variant in the M3 domain (c.1999G>A, p.Val667Ile) has been reported in three unrelated individuals  (Li. 2016. PubMed ID: 27616483 Xiang Wei et al. 2019. PubMed ID: 31504254). Haploinsuficiency due to chain-terminating variants is not an established mechanism of disease; however, there is limited evidence associating this mechanism with autism spectrum disorder and schizophrenia (Yu. 2018. PubMed ID: 29317596).

GRIN2D(GluN2D)-knockout mice are viable and overtly normal. However, close examination revealed they have mild differences in locomotor phenotype and spatial memory, as well as altered monoamine levels, cellular electrophysiology characteristics, and interneuron histology (Camp and Yuan. 2020. PubMed ID: 31918992). Therefore, this gene is not essential for cellular function. Instead, it appears to be required for regulating complex neurodevelopmental functions of vertebrate organisms.  

GRIN2D encodes the alpha-2 subunit of 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 (Camp and Yuan. 2020. PubMed ID: 31918992).

The clinical sensitivity of this test alone is expected to be low (<1%). GRIN2D-related developmental and epileptic encephalopathy is an ultra-rare disorder with only 16 unique missense variants reported to date. In addition, there are approximately one hundred genes associated with similar epileptic encephalopathy phenotypes. However, since all well-characterized pathogenic variants in GRIN2D are 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 GRIN2D 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.