Intellectual Disability via the GRIK2 Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD).

Deficiency of Glutamate receptor ionotropic kainite 2 (GRIK2) primarily leads to mental retardation type 6 (MRT6); however there is at least one report of a gain of function pathogenic variant in GRIK2. GRIK-related intellectual disability can be both non-syndromic and syndromic. The clinical features may include (but may not be limited to) intellectual disability, developmental delay, motor and speech delay, epilepsy, ataxia, hypotonia, dystonia, microcephaly, behavioral problems including autism, happy demeanor, short attention span, stereotypic behavior, and bouts of laughter (Motazacker et al. 2007. PubMed ID: 17847003; Najmabadi et al. 2007. PubMed ID: 17120046; Cordoba et al. 2015. PubMed ID: 25039795; Guzmán et al. 2017. PubMed ID: 28180184; Monies et al. 2017. PubMed ID: 28600779; https://gene.sfari.org/database/human-gene/GRIK2).

GRIK2-related (also described as GLUR6) intellectual disability is primarily transmitted in autosomal recessive manner; however there is at least one report of a de novo pathogenic variant (Guzmán et al. 2017. PubMed ID: 28180184). GRIK2 maps to chromosome 6q16.3 and encodes a 908 amino acid polypeptide subunit of kainate receptors (KARs). Glutamate receptor ionotropic kainite 2 (GRIK2) is a SUMO (small ubiquitin-like modifier protein) substrate and is presumed to play role in excitatory neurotransmission in the brain, induction of long-term potentiation and axonal Ca⁺⁺ homeostasis (Contractor et al. 2001. PubMed ID: 11182092; Martin et al. 2007. PubMed ID: 17486098; Ouardouz et al. 2009. PubMed ID: 19224535). To date, missense, nonsense and splice site variants have been reported, and there is at least one report of a complex rearrangement (Human Gene Mutation Database).

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795).

This test provides full coverage of all coding exons of the GRIK2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).