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GRIN1-Related Neurodevelopmental Disorder

Synonyms: GRIN1-Related Developmental and Epileptic Encephalopathy

, MD and , MD.

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Estimated reading time: 19 minutes

Summary

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 problems. 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. When the GRIN1 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 germline 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 diagnosis are possible.

Diagnosis

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 (DD) or intellectual disability (ID)
    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 shows a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. See Figure 1.

Figure 1.

Figure 1.

Brain MRI findings of polymicrogyria in children with GRIN1 neurodevelopmental disorder demonstrating bilateral extensive polymicrogyria (white arrows) that is more severe anteriorly Note in most images (except I): Increased extra-axial spaces and enlarged (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 missense variant in GRIN1 (64 individuals have been reported)
  • Biallelic pathogenic missense or truncating variants in GRIN1 (8 individuals from 4 families have been reported)

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).

Option 1

A multigene panel that includes GRIN1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and 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. Of note, given the rarity of GRIN1-related neurodevelopmental disorder, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, yields results similar to a multigene panel but has two advantages:

  • A multigene panel may not include all rare genes recently identified as causing ID; and
  • Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.

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.

Table 1.

Molecular Genetic Testing Used in GRIN1-Related Neurodevelopmental Disorder

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
GRIN1Sequence analysis 3100%
Gene-targeted deletion/duplication analysis 4Unknown 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) 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 antiepileptic drugs was available, 17 had refractory seizures and ten were well controlled with standard antiepileptic drugs.

Other neurologic findings

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

Behavioral problems. Signs of autism spectrum disorder were observed in 22%. Other behavioral problems 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.

Differential Diagnosis

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

Management

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.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with GRIN1-Related Neurodevelopmental Disorder

System/ConcernEvaluationComment
EyesOphthalmologic evaluationAssessment for cortical visual impairment & oculogyric crisis
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team evaluationAssessment for feeding difficulties, nutrition, weight gain, constipation, & gastroesophageal reflux disease
MusculoskeletalOrthopedics / physical medicine & rehabilitation / physical therapy (PT) / occupational therapy (OT) evaluationExamination for muscular hypotonia, spasticity, & scoliosis
To incl assessment of:
  • Gross motor & fine motor skills
  • Contractures, clubfoot, & kyphoscoliosis
  • Mobility & activities of daily living & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
NeurologicNeurologic evaluationIncl clinical evaluation for movement disorders, seizures, EEG, & brain MRI
DevelopmentDevelopmental assessmentTo incl:
  • Evaluation of motor, speech/language, general cognitive, & vocational skills
  • Motor, adaptive, cognitive, & speech/language evaluation
  • Evaluation for early intervention / special education
Psychiatric/
Behavioral
Neuropsychiatric evaluationFor individuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD
Miscellaneous/
Other
Family supports/resourcesAssess:
  • Use of community or online resources such as Parent to Parent
  • Need for social work involvement for parental support
  • Need for home nursing referral
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

Treatment of Manifestations

Table 3.

Treatment of Manifestations in Individuals with GRIN1-Related Neurodevelopmental Disorder

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay / Intellectual disabilitySee Developmental Delay - Intellectual Disability Educational Issues
Central visual impairmentNo specific treatment; early intervention w/vision therapy may help to stimulate visual development.
SeizuresStandardized treatment w/AEDs by an experienced neurologist
  • Many different AEDs may be effective, & no one AED has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Muscular hypotonia, spasticity, & movement disorderOrthopedics / physical medicine & rehabilitation / PT / OT incl stretching to help prevent contractures & fallsConsider need for positioning & mobility devices, disability parking placard

AEDs = antiepileptic drugs; OT = occupational therapy; PT = physical therapy

1.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Developmental Delay / Intellectual Disability Educational Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; however, for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine if any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has AAC expertise. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Table 4.

Recommended Surveillance for Individuals with GRIN1-Related Neurodevelopmental Disorder

System/ConcernEvaluationFrequency
EyesOphthalmologic evaluationAt time of diagnosis & then as clinically indicated
GastrointestinalFeeding, nutrition status, weight gainAs clinically indicated
MusculoskeletalExamination for muscular hypotonia, spasticity, & scoliosisAs clinically indicated
NeurologicMonitor those w/seizures.As clinically indicated
PsychiatricBehavioral assessment for anxiety, attention, & aggressive or self-injurious behaviorAs clinically indicated
Miscellaneous/
Other
Monitor developmental progress & educational needs.As clinically indicated

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

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 estimated to be 1% because of the theoretic possibility of parental germline mosaicism [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

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 (Heterozygote) 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 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Autosomal recessive inheritance. Once the GRIN1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

GRIN1-Related Neurodevelopmental Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
GRIN19q34​.3Glutamate receptor ionotropic, NMDA 1GRIN1 databaseGRIN1GRIN1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for GRIN1-Related Neurodevelopmental Disorder (View All in OMIM)

138249GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 1; GRIN1
614254NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT; NDHMSD
617820NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL RECESSIVE; NDHMSR

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 related-object://gene,grin1-ndd,grin1-ndd.molgen.TA/, 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].

References

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Chapter Notes

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

humangenetik.uniklinikum-leipzig.de
www.grin-database.de

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 decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.

Revision History

  • 20 June 2019 (bp) Review posted live
  • 28 February 2019 (kp) Original submission
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