Clinical characteristics.

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues. A subset of individuals show a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. To date, 72 individuals with GRIN1-NDD have been reported.

Diagnosis/testing.

The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported).

Management.

Treatment of manifestations: Standard treatment of DD/ID, seizures, feeding problems, and behavioral issues.

Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.

Genetic counseling.

GRIN1-NDD is inherited in either an autosomal dominant or autosomal recessive manner:

• Autosomal dominant inheritance: All probands with a heterozygous GRIN1 pathogenic variant reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant. If the GRIN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the theoretic possibility of parental mosaicism.
• Autosomal recessive inheritance: At conception, each sib of an individual with biallelic GRIN1 pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the GRIN1-NDD pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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 Figure 1.

Figure 1.

Brain MRI findings of polymicrogyria in children with GRIN1 neurodevelopmental disorder demonstrating bilateral extensive polymicrogyria (white arrowheads) that is more severe anteriorly Note in most images (except I): Increased extra-axial spaces and (more...)

Establishing the Diagnosis

The diagnosis of GRIN1-related neurodevelopmental disorder is established in a proband who has one of the following on molecular genetic testing (see Table 1):

• A heterozygous de novo pathogenic (or likely pathogenic) missense variant in GRIN1 (64 individuals have been reported)
• Biallelic pathogenic (or likely pathogenic) missense or truncating variants in GRIN1 (8 individuals from 4 families have been reported)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Because the phenotype of GRIN1-related neurodevelopmental disorder is often nonspecific and indistinguishable from many other inherited disorders, it is most likely to be diagnosed by either gene-targeted testing (i.e., a multigene panel) (see Option 1) or genomic testing (which does not require the clinician to determine which gene is likely involved) (see Option 2).

Clinical Description

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability in all affected individuals. Epilepsy (seen in 65%), muscular hypotonia (66%), and movement disorders (48%) are common manifestations.

To date, 72 individuals with GRIN1-NDD have been reported, including 64 individuals with de novo heterozygous pathogenic missense variants and eight individuals from four families with biallelic pathogenic missense or truncating variants [Firth et al 2009, Hamdan et al 2011, Allen et al 2013, Redin et al 2014, Farwell et al 2015, Ohba et al 2015, Zhu et al 2015, Bosch et al 2016, Halvardson et al 2016, Helbig et al 2016, Kobayashi et al 2016, Lemke et al 2016, Retterer et al 2016, Vanderver et al 2016, Chen et al 2017, Ortega-Moreno et al 2017, Rossi et al 2017, Tan et al 2017, Zehavi et al 2017, Dillon et al 2018, Fry et al 2018, Paderova et al 2018, Papa et al 2018, Pironti et al 2018, Staněk et al 2018]. The following description of the phenotypic spectrum associated with GRIN1-NDD is based on these reports. In 62 of the 72 reported individuals, clinical information was sufficient to draw conclusions on the overall phenotype (54 individuals heterozygous for a de novo missense variant and 8 individuals with homozygous variants). Of note, phenotypic data on 11 individuals with a heterozygous de novo variant comes from the DECIPHER database.

Developmental delay (DD) and intellectual disability (ID). All affected individuals have a variable degree of DD or ID (profound in 17%, severe in 71%, moderate in 7%, mild in 5%). No active speech has been noted in 48% of individuals.

Epilepsy. Seizures occurred in 65% of individuals. Some affected individuals presented with different seizure types over time. Where specified, seizures have been classified as epileptic spasms (13%), generalized seizures (68%), and focal seizures (20%). Seizure types reported among generalized and focal seizures comprise tonic, tonic-clonic, atonic, and/or myoclonic seizures, bilateral eyelid myoclonus, focal dyscognitive seizures, absence seizures, focal motor seizures, gelastic seizures, and status epilepticus.

Onset of seizures ranged from birth to 11 years with a median onset of 22.5 months. In 27 individuals on whom follow up or outcome on treatment with anti-seizure medication was available, 17 had refractory seizures and ten were well controlled with standard anti-seizure medication.

Other neurologic findings

• Muscular hypotonia (in 66%)
• Spasticity (40%)
• Movement disorders (48%); where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
• Cortical visual impairment (34%)
• Oculogyric crisis (11%)

Behavioral findings. Signs of autism spectrum disorder were observed in 22%. Other behavior issues included stereotypic movements (32%), self-injurious behavior (7%), and sleep disorder (15%).

Feeding difficulties / gastrointestinal abnormalities. Feeding difficulties were reported in 31% of individuals. Severe muscular hypotonia, gastroesophageal reflux, or oral-pharyngeal dysphagia with chewing and swallowing difficulty caused persistent feeding problems, requiring G-tube insertion in a subset of individuals.

Growth. Growth restriction or short stature was seen in 11% while microcephaly was documented in 27%.

Neuroimaging. A malformation of cortical development (MCD) consisting of extensive diffuse bilateral polymicrogyria has been seen in 11 individuals [Fry et al 2018]. Polymicrogyria-affected brain regions comprised frontal, perisylvian, parietal, and temporal areas with some occipital sparing. Additional variable findings included increased extra-axial spaces, enlarged lateral ventricles, reduced white matter volume, thinning of the corpus callosum, and abnormal hippocampi. The MCD was similar in appearance to tubulinopathy-related or GRIN2B-related dysgyria [Platzer et al 2017]. See GRIN2B-Related Neurodevelopmental Disorder.

Other signs repeatedly noted in individuals without an MCD were generalized volume loss or cerebral atrophy (23%).

Signs of a leukoencephalopathy have been noted in two individuals with nonspecific hyperintensities of the white matter [Vanderver et al 2016, Pironti et al 2018].

Other

• Scoliosis has been seen in 11% of affected individuals.
• No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.

Prognosis. Psychomotor regression or loss of acquired skills has specifically been noted in one individual starting at age 3.5 years with loss of speech, impaired social interaction, drooling, and loss of sphincter control [Papa et al 2018].

It is unknown if life span in GRIN1-NDD is abnormal. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

De novo heterozygous pathogenic variants in individuals with a malformation of cortical development (MCD) are located in the domains S2 and M3 [Fry et al 2018]. 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 [Lemke et al 2016]. A comparable clinical course has not been reported in the five individuals with homozygous GRIN1 missense variants located in the amino-terminal domain [Bosch et al 2016, Lemke et al 2016, Rossi et al 2017] 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.

Penetrance

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

Prevalence

The prevalence of GRIN1-NDD in the general population is unknown. To date, reports on fewer than 100 individuals have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIN1-NDD, the evaluations summarized in Table 2 (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

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

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is inherited in one of two ways:

• In an autosomal dominant manner, typically caused by a de novo pathogenic missense variant
• In an autosomal recessive manner

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• All probands reported to date with autosomal dominant GRIN1-NDD whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the GRIN1 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 pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the GRIN1 pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the GRIN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the theoretic possibility of parental mosaicism.
• 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]. This frequency results in an increased recurrence risk to sibs, which is estimated to be 1% [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with a GRIN1-NDD has a 50% chance of inheriting the GRIN1 pathogenic variant.
• Individuals with GRIN1-NDD are not known to have reproduced; however, many are not yet of reproductive age.

Other family members. Given that all probands with autosomal dominant GRIN1-NDD reported to date have the disorder as a result of a de novo GRIN1 pathogenic variant, the risk to other family members is presumed to be low.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive GRIN1-NDD are obligate heterozygotes (i.e., carriers of one GRIN1 pathogenic variant).
• To date, heterozygous (carrier) parents have been asymptomatic and, thus, are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous (carrier) sibs are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with GRIN1-NDD are not known to have reproduced.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a GRIN1 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the GRIN1 pathogenic variants in the family.

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

Autosomal dominant inheritance. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo GRIN1 pathogenic variant. However, there is a frequency of (inferred) germline mosaicism of 10% and a consecutive recurrence risk to sibs of 1% based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016, Myers et al 2018]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Autosomal recessive inheritance. Once the GRIN1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Autosomal dominant and autosomal recessive inheritance. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. 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. NMDARs are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by GRIN1) and two glutamate-binding GluN2 subunits (encoded by 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. The GluN1 subunit is ubiquitously expressed from embryonic stage to adulthood [Paoletti et al 2013]. Although the GluN1 subunit is encoded by a single gene (GRIN1), alternative splicing results in eight isoforms. There are differences in GluN1 isoform expression, but its functional significance is unclear.

Gene structure. The GRIN1 transcript deemed clinically most relevant (NM_007327.3) comprises 20 exons. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. In autosomal dominant GRIN1-NDD, only de novo missense variants have been reported to date. De novo missense variants cluster within or in close proximity to the ligand-binding domain S2 as well as the transmembrane domains M1-M4 [Lemke et al 2016]. No de novo truncating variants deemed to be causative have been reported to date.

In autosomal recessive GRIN1-NDD, three families with a homozygous missense variant located in the amino-terminal domain and one family with three affected individuals with a homozygous nonsense variant have been reported [Bosch et al 2016, Lemke et al 2016, Rossi et al 2017].

Normal gene product. The isoform deemed clinically most relevant (NP_015566.1) consists of 938 amino acids and contains an amino-terminal domain, two ligand-binding domains (S1 and S2), four transmembrane domains (M1-M4), a calmodulin domain, and a C-terminal domain.

Abnormal gene product. Functional evaluation of missense variants has determined that some cause loss of function and some cause gain of function of the NMDA receptor [Lemke et al 2016, Fry et al 2018, Xiangwei et al 2018].

Author Notes

Konrad Platzer, MD
Institute of Human Genetics
University of Leipzig Medical Center
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany

Johannes R Lemke, MD
Institute of Human Genetics
University of Leipzig Medical Center
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany

Institute of Human Genetics
GRIN Database

Acknowledgments

This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from www.deciphergenomics.org and via email from contact@deciphergenomics.org. Funding for the project was provided by the Wellcome Trust.

Revision History

• 1 April 2021 (aa) Revision: incorporated parental mosaicism data from Myers et al [2018]
• 20 June 2019 (bp) Review posted live
• 28 February 2019 (kp) Original submission

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