ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20890276 Endele et al. (2010): Discusses a heterozygous c.652C>T transition, resulting in a premature stop codon (p.Q218X), in a 4-year-old individual with mild to moderate intellectual disability and abnormal EEG. His mother and maternal grandmother also carried the c.652C>T mutation, and both had a history of seizures during early childhood. RNA analysis in the proband revealed monoallelic expression of the wild-type allele, suggesting that GRIN2A transcripts with the PTC were efficiently degraded by nonsense-mediated mRNA decay. This change was not observed in 360 control chromosomes.

Haploinsufficiency phenotype comments:

Endele et al. 2010 (discussed above) also describe an individual with a t(16;17)(p13.2;q11.2), deleting exons 4-6 of GRIN2A. The individual was a 25-year-old male with a history of febrile seizures followed by tonic-clonic seizures and severe intellectual disability. His father, paternal aunt, and cousin, who also carry the translocation, had a history of grand-mal seizures with onset at the end of their first decade that spontaneously decreased during adolescence. All four family members had behavioral problems, and the cousin also had moderate intellectual disability. They also discuss a heterozygous de novo c.1845C>A (p.N615K) transversion found in a 3-year-old girl with early-onset epileptic encephalopathy, abnormal EEG and severe developmental delay (not observed in 1080 control chromosomes). The authors hypothesize that disruption of GRIN2A in the translocation subjects and the nonsense alteration p.Q218X most likely lead to functional null alleles associated with a relatively mild phenotype comprising epilepsy and variable cognitive impairment, but that the more severe phenotype in the subject with p.N615K can be explained by a dominant negative effect on NMDA receptor function. Additionally, Reutlinger et al (2010, PMID: 20384727) report three individuals with epilepsy, developmental disabilities, and variable dysmorphic features or congenital anomalies who each had a deletion involving GRIN2A. When the three deletions were compared, GRIN2A is the only gene located within the smallest region of overlap. Two of these deletions were de novo; inheritance was not tested for the third. Also of note: In an exome study of individuals with unexplained severe intellectual disability (PMID:23033978), de Ligt et al. found two heterozygous de novo missense mutations in GRIN2A. The first, a 1945C-G transversion resulting in a leu649-to-val (L649V) substitution, was found in a patient with severe intellectual disability, dysplastic corpus callosum, myelination delay, epilepsy, severe feeding problems, hypothyroidism, and mild facial dysmorphism. The second, a 1655C-G transversion resulting in a pro522-to-arg (P522R) substitution, was found in a patient with severe intellectual disability, no speech, epilepsy since 9 months of age, and spasticity. Also of note: PMID: 22833210, Tarabeux 2011: "Two de novo mutations were identified in the GRIN2A gene. The first in a patient with SCZ [schizophrenia] with no familial history of SCZ was a missense (c.2902G>A; p.A968T) located in the intracellular domain of the protein. It was not predicted as having important functional consequence based on in silico analysis (SIFT, PolyPhen and SNAP; Table 2); nevertheless, it modified an amino acid that is highly conserved in mammals. The second one was a silent mutation, c.3669C>T identified in another patient with sporadic SCZ, and was not predicted to be damaging by in silico analysis. Paternal age was 39 and maternal age was 29 for this patient. These mutations were not found in the remaining 1707 chromosomes that had been sequenced. None of these patients had a mental retardation with 11 and 12 years of education, respectively."

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity