Intellectual disabilityGene: GRIN2D Green List (high evidence)
Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Created: 7 Jan 2019, 11:57 a.m.
Green List (high evidence)
Heterozygous pathogenic variants in GRIN2D cause Epileptic encephalopathy, early infantile, 46 (MIM 617162).
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 or 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 for individuals with such variants (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).
Created: 6 Dec 2018, 2 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Epileptic encephalopathy, early infantile, 46 (MIM 617162)
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: GRIN2D were changed from Epileptic encephalopathy, early infantile, 46 (MIM 617162) to Epileptic encephalopathy, early infantile, 46, 617162; intellectual disability
Gene: grin2d has been classified as Green List (High Evidence).
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.