Clinical characteristics.

GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported.

Diagnosis/testing.

The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing.

Management.

Treatment of manifestations: DD/ID, muscle tone abnormalities (spasticity, hypotonia, and feeding difficulties), epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice.

Surveillance: Of clinical manifestations as clinically indicated.

Genetic counseling.

GRIN2B-related neurodevelopmental disorder is inherited in an autosomal dominant manner. All probands reported to date with a GRIN2B-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN2B pathogenic variant or deletion. If the proband represents a simplex case (i.e., the only affected family member) and the GRIN2B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Suggestive Findings

GRIN2B-related neurodevelopmental disorder should be considered in individuals with the following clinical and/or brain MRI findings.

Clinical findings

• Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
• Any of the following features presenting in infancy or childhood:
  • Epilepsy
  • Autism spectrum disorder / behavioral issues
  • Microcephaly
  • Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
  • Dystonic, dyskinetic, or choreiform movement disorder
  • Cortical visual impairment

Brain MRI findings. MRI reveals a malformation of cortical development (MCD) consisting of diffuse cortical dysplasia including polymicrogyria, hypoplastic corpus callosum, enlarged/dysplastic basal ganglia, and hippocampal dysplasia. The MCD can also resemble the tubulinopathies spectrum (see Tubulinopathies Overview).

Establishing the Diagnosis

The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic (or likely pathogenic) variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing (see Table 1).

Note: (1) Larger contiguous-gene deletions including but not limited to GRIN2B are not discussed in this GeneReview. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of a heterozygous GRIN2B variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include use of a multigene panel, chromosomal microarray analysis, and/or more comprehensive genomic testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many disorders with intellectual disability overlap, most children with GRIN2B-related neurodevelopmental disorder are diagnosed by genomic testing. Note: Single-gene testing (sequence analysis of GRIN2B, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes GRIN2B and other genes of interest (see Differential Diagnosis) typically provides the best opportunity to identify the genetic cause of the condition while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For GRIN2B-related disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GRIN2B) that cannot be detected by sequence analysis.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

GRIN2B-related neurodevelopmental disorder is characterized in all affected individuals by mild to profound developmental delay / intellectual disability (DD/ID). Epilepsy (seen in 51%) and autism spectrum disorder (ASD) and autistic-like behaviors (26%) are common. Other infantile- or childhood-onset findings include microcephaly; muscle tone abnormalities (hypotonia, spasticity); dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported in cohorts of individuals with DD/ID/ASD, early-onset epilepsy, and malformations of cortical development (MCD).

Unless otherwise noted, the information in this section is based on extended data of Platzer et al [2017]. Detailed clinical assessment was available for 61 affected individuals, with specification of ID in 54. Brain MRI was performed in 47 individuals.

Brain Imaging

A malformation of cortical development (MCD) has been seen in six (13%) of 47 individuals; the diffuse cortical dysplasia was consistent with that of polymicrogyria. Cortical findings included a mixture of large and small gyri separated by shallow sulci (Figure 1). The gray-white border appeared smooth.

Figure 1.

MRI of individuals with malformation of cortical development A-D: patient 1; E-H: patient 2; I-L: patient 3; M-P: patient 4; Q-T: patient 5; U-X: patient 6; AA-DD: normal control

Other findings included the following:

• Hypoplastic corpus callosum of varying degrees
• Enlarged and mildly dysplastic basal ganglia
• Hippocampal dysplasia with thick leaves and open hilus
• Enlarged tecta
• Absent septum pellucidum

The malformation of cortical development is also consistent with that of tubulinopathies (see Tubulinopathies Overview). The identified individuals with MCD display a very similar degree of severity, and there are no reports of affected individuals with less pronounced malformations of cortical development.

Generalized cerebral volume loss indicating cerebral atrophy was seen in four other individuals (9%, 4/47).

Genotype-Phenotype Correlations

Variant class and intellectual outcome show a significant correlation: heterozygotes for a GRIN2B pathogenic variant resulting in a null allele (e.g., nonsense or frameshift variants, deletion involving whole exons or the entire gene, translocation and inversion disrupting GRIN2B) tended to display mild or moderate ID, while heterozygotes for pathogenic missense variants displayed severe ID (Fisher's exact test, p=0.0079) [Platzer et al 2017].

Missense variants in GRIN2B that cause a malformation of cortical development are located in transmembrane domain M3, in the ligand-binding domain S2, and in the linker between S2 and the transmembrane domain M4, a finding consistent with GRIN1 variants causing an MCD [Fry et al 2018] (see GRIN1-Related Neurodevelopmental Disorder).

Penetrance

Penetrance of GRIN2B-related neurodevelopmental disorder is thought to be 100%.

Prevalence

The prevalence of GRIN2B-related neurodevelopmental disorder in the general population is unknown. To date, fewer than 100 individuals have been reported.

The prevalence of GRIN2B-related neurodevelopmental disorder among individuals with neurodevelopmental disorders and/or childhood-onset epilepsy is around 0.2% [Platzer et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIN2B-related neurodevelopmental disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In vitro studies on oocytes of Xenopus laevis suggest a beneficial treatment response of pathogenic missense GRIN2B gain-of-function variants to blockers of the N-methyl D-aspartate receptor (e.g., memantine, radiprodil) [Lemke et al 2014, Mullier et al 2017, Platzer et al 2017]. However, a significant clinical benefit from treatment with such compounds has not yet been demonstrated [Platzer et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

GRIN2B-related neurodevelopmental disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date all probands with a GRIN2B-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN2B pathogenic variant or GRIN2B exon or whole-gene deletion.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo genetic alteration.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a genetic alteration from a parent with germline mosaicism. Although parental germline mosaicism has not been reported to date, molecular genetic tests sensitive enough to detect low-level germline mosaicism (e.g., allele-specific PCR, next-generation sequencing methods) may be considered.
• Theoretically, if the parent is the individual in whom the GRIN2B genetic alteration first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [Stosser et al 2018].

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the proband represents a simplex case (i.e., the only affected family member) and the GRIN2B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism [Rahbari et al 2016].
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [Myers et al 2018].

Offspring of a proband. Individuals with a GRIN2B-related neurodevelopmental disorder are not known to reproduce.

Other family members. Given that all probands with a GRIN2B-related neurodevelopmental disorder reported to date have the disorder as a result of a de novo genetic alteration, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo GRIN2B pathogenic variant or deletion of GRIN2B. However, based on the theoretic possibility of parental mosaicism (reported to be 10% in one study on apparently asymptomatic parents of children with developmental and epileptic encephalopathy [Myers et al 2018]), the recurrence risk to sibs is estimated to be 1% [Rahbari et al 2016]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels expressed throughout the brain mediating excitatory neurotransmission. Signaling via NMDAR plays an important role in brain development, learning, memory, and other higher cognitive functions. NMDAR are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by GRIN1) and two glutamate-binding GluN2 subunits (GRIN2A through GRIN2D) [Traynelis et al 2010]. Simultaneous binding of both agonists activates the NMDAR, which opens a cation-selective pore leading to an influx of Ca²⁺ and depolarization.

Compared with the ubiquitously expressed GluN1 subunits, the GluN2 subunits show specific spatiotemporal expression profiles throughout the central nervous system [Paoletti et al 2013]. The GluN2B and GluN2D subunits are expressed prenatally, whereas expression of the GluN2A and GluN2C subunits significantly increases shortly after birth. Over time, postnatal expression of GluN2B is progressively restricted to the forebrain in rat and mouse models.

Gene structure. GRIN2B spans about 400 kb of genomic DNA and comprises 13 exons (transcript NM_000834.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Missense, nonsense, frameshift, and splicing pathogenic variants have been reported (see Table A, Locus-Specific Databases) [Endele et al 2010, Tarabeux et al 2011, de Ligt et al 2012, O'Roak et al 2012, Allen et al 2013, Dimassi et al 2013, Freunscht et al 2013, Adams et al 2014, Hamdan et al 2014, Kenny et al 2014, Lemke et al 2014, O'Roak et al 2014, Deciphering Developmental Disorders Study Group 2015, Grozeva et al 2015, Yavarna et al 2015, Zhang et al 2015, Zhu et al 2015, Bosch et al 2016, Retterer et al 2016, Smigiel et al 2016, Platzer et al 2017].

Of note, discussion of the phenotypes associated with large rearrangements at 12p13.1 that involve GRIN2B – and often contiguous genes – have not been included in this GeneReview because the observed clinical findings cannot be attributed with assurance solely to GRIN2B. Nonetheless, these deletions [Dimassi et al 2013], translocations, apparently balanced chromosome rearrangements, and inversions [Endele et al 2010, Talkowski et al 2012] are mentioned here for completeness. Three interstitial deletions in 12p13.1 involving parts of GRIN2B are non-recurrent and range in size from 0.58 Mb to 4.1 Mb [Dimassi et al 2013]. All deletions involve neighboring genes: the shortest one resulted in a deletion of the first exon of GRIN2B and the neighboring gene ATF7IP, which corresponds to the minimal region of overlap; the other two deletions comprise 29 and 21 neighboring genes.

Normal gene product. The protein consists of 1,484 amino acids and contains an amino-terminal domain, two ligand-binding domains (S1 and S2), four transmembrane domains (M1-M4), and a C-terminal domain.

Abnormal gene product. Pathogenic missense variants cluster within or in very close proximity to the ligand-binding domains S1 and S2, as well as the transmembrane domains M1-M4 [Platzer et al 2017].

Author Notes

Konrad Platzer, MD
Institute of Human Genetics
University of Leipzig Hospitals and Clinics
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany

Johannes R Lemke, MD
Institute of Human Genetics
University of Leipzig Hospitals and Clinics
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany

Institute of Human Genetics

GRIN Database

Revision History

• 25 March 2021 (aa) Revision: incorporated parental mosaicism data from Myers et al [2018]
• 31 May 2018 (bp) Review posted live
• 30 October 2017 (jrl) Original submission

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