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Intellectual disability - microarray and sequencing v3.1271 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Intellectual disability - microarray and sequencing v2.576 GRIN2D Konstantinos Varvagiannis gene: GRIN2D was added
gene: GRIN2D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GRIN2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GRIN2D were set to 27616483; 30280376
Phenotypes for gene: GRIN2D were set to Epileptic encephalopathy, early infantile, 46 (MIM 617162)
Penetrance for gene: GRIN2D were set to unknown
Review for gene: GRIN2D was set to GREEN
gene: GRIN2D was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in GRIN2D cause Epileptic encephalopathy, early infantile, 46 (MIM 617162).

As commented in the previous review, PMID: 27616483 is the first report on 2 unrelated individuals with severe epileptic encephalopathy (onset of seizures at the age of 2 and 4 months). Severe DD with ID was noted in both.

Each of these individuals were heterozygous for the same missense variant (NM_000836.2:c.1999G>A p.Val667Ile) as a de novo event. Functional studies demonstrated a gain-of-function effect.

GRIN2D encodes for an NMDA receptor subunit, and the gain-of-function effect shown for this variant suggests that NMDAR antagonists might be useful as adjuvant therapy (some improvement noted in both individuals).

[The mode of pathogenicity selected here may be modified as more evidence on further variants becomes available. GRIN2D appears to be intolerant also to LoF mutations with a pLI of 1. Both LoF and GoF mutations have been described for genes encoding other NMDAR subunits].

PMID: 30280376 reports on 3 additional unrelated patients with developmental and epileptic encephalopathy and pathogenic or likely pathogenic missense variants in GRIN2D.

Three additional missense variants are reported (Met681Ile, Ser694Arg, Asp449Asn). Parental studies were possible only for the patient with Met681Ile (de novo) as well as for the individual with Ser694Arg (only one parent available though).

Significant developmental delay was evident in all prior to the onset of seizures (1m/2y/3y respectively) and subsequent developmental stagnation/regression with ID.

The phenotype of these 3 individuals as well as of the 2 previously described is summarized in table 1 of the latter article.

GRIN2D is a probable DD gene in G2P and is included in gene panels for ID offered by diagnostic laboratories.

Several other genes for NMDA receptor subunits (eg. GRIN2A, GRIN2B, GRIN1) and relevant/similar phenotypes are included in this panel as green.

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.468 GRIN1 Louise Daugherty Source Victorian Clinical Genetics Services was added to GRIN1.
Intellectual disability - microarray and sequencing GRIN1 Louise Daugherty edited their review of GRIN1
Intellectual disability - microarray and sequencing GRIN1 Louise Daugherty classified GRIN1 as Green List (high evidence)
Intellectual disability - microarray and sequencing GRIN1 BRIDGE consortium edited their review of GRIN1
Intellectual disability - microarray and sequencing GRIN1 BRIDGE consortium reviewed GRIN1
Intellectual disability - microarray and sequencing GRIN1 Ellen Thomas classified GRIN1 as amber
Intellectual disability - microarray and sequencing GRIN1 Ellen Thomas classified GRIN1 as amber
Intellectual disability - microarray and sequencing GRIN1 Ellen Thomas classified GRIN1 as amber
Intellectual disability - microarray and sequencing GRIN1 Ellen Thomas classified GRIN1 as amber
Intellectual disability - microarray and sequencing GRIN1 Ellen Thomas commented on GRIN1