Clinical Guidance

De novo heterozygous pathogenic variants in individuals with a malformation of cortical development (MCD) are located in the domains S2 and M3 . As there are only a few individuals with causative GRIN1 variants in these regions who do not have an MCD, a genotype-phenotype correlation is possible. All three children from a family with a homozygous nonsense GRIN1 variant displayed a fatal developmental epileptic encephalopathy leading to death between ages five days and five months . A comparable clinical course has not been reported in the five individuals with homozygous GRIN1 missense variants located in the amino-terminal domain or in any individual with a de novo variant. The heterozygous parents of children homozygous for GRIN1 variants did not show any manifestations of GRIN1-NDD.

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"

Penetrance

Penetrance of GRIN1-related neurodevelopmental disorder is thought to be 100%.

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"

Diagnostic Criteria

Formal diagnostic criteria for GRIN1-related neurodevelopmental disorder have not been established.

Suggestive Findings

GRIN1-neurodevelopmental disorder (GRIN1-NDD) should be considered in individuals with the following clinical and/or brain MRI findings.

Clinical findings

• Mild-to-profound developmental delay or intellectual disability

AND

• Any of the following presenting in infancy or childhood:

• Epilepsy

• Muscular tone abnormalities such as hypotonia and spasticity

• Dystonic, dyskinetic, or choreiform movement disorder

• Autism spectrum disorder

• Microcephaly

• Cortical visual impairment

Brain MRI findings. A subset of individuals show a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. See .

Establishing the Diagnosis

The diagnosis of GRIN1-related neurod...

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"

Differential Diagnosis

Because the phenotypic features associated with GRIN1-related neurodevelopmental disorder are not sufficient to diagnose this condition, all disorders with the following features should be considered in the differential diagnosis:

• Intellectual disability without other distinctive findings (See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series.)

• Early-onset epileptic encephalopathy (See OMIM Phenotypic Series.)

• Polymicrogyria

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GRIN1-NDD, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 2. Recommended Evaluations Following Initial Diagnosis in Individuals with GRIN1-Related Neurodevelopmental Disorder

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"

Therapies Under Investigation

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 — "GRIN1-Related Neurodevelopmental Disorder"

Surveillance Guidelines

Table 4.

Recommended Surveillance for Individuals with GRIN1-Related Neurodevelopmental Disorder

System/Concern | Evaluation | Frequency

Eyes | Ophthalmologic eval | At time of diagnosis then as clinically indicated

Gastrointestinal

| Feeding, nutrition status, weight gain | As clinically indicated

Musculoskeletal

| Exam for muscular hypotonia, spasticity, scoliosis

Neurologic

| Monitor those w/seizures.

Psychiatric

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

Miscellaneous/

Other

| Monitor developmental progress educational needs.

Source: GeneReviews — "GRIN1-Related Neurodevelopmental Disorder"