Clinical Guidance

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) . 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 (see GRIN1-Related Neurodevelopmental Disorder).

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"

Penetrance

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

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"

Diagnostic Criteria

Formal diagnostic criteria for GRIN2B-related neurodevelopmental disorder have not been established.

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

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"

Differential Diagnosis

Phenotypic features associated with heterozygous GRIN2B pathogenic variants are not sufficient to diagnose GRIN2B-related neurodevelopmental disorder. All genes known to be associated with ID, early-onset epileptic encephalopathy, and malformations of cortical development (especially diffuse polymicrogyria and tubulinopathies) should be included in the differential diagnosis of GRIN2B-related neurodevelopmental disorder as individuals with GRIN2B-related neurodevelopment disorder can present with a combination of clinically unspecific phenotypes such as DD/ID/ASD and/or epilepsy. The underlying genetic causes of these phenotypes comprise a very heterogeneous group of disorders, as is the case with tubulinopathies, polymicrogyria, and their differential diagnoses. Table 2. Genes to Consider in the Differential Diagnosis of GRIN2B-Related Neurodevelopmental Disorder

Management Guidelines

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

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"

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) . However, a significant clinical benefit from treatment with such compounds has not yet been demonstrated . 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.

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with GRIN2B-Related Neurodevelopmental Disorder

System/Concern | Evaluation | Frequency

Ocular

| Ophthalmologic | As clinically indicated

Gastrointestinal

| Feeding, nutrition status, weight gain

Musculoskeletal

| Monitor gross fine motor development in those w/tone abnormalities.

Neurologic

| Monitor treatment effectiveness in those w/seizures, movement disorders, /or spasticity.

Psychiatric

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Miscellaneous/

Other

| Monitor developmental progress educational needs.

Source: GeneReviews — "GRIN2B-Related Neurodevelopmental Disorder"