Submission Details

GRIK2 was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2007 by Motazacker et al (PMID: 17847003). Clinical features include intellectual disability, social and cognitive impairment, epilepsy, dystonia, and behavioral disorders. Variants in GRIK2 have also been associated with autosomal dominant complex neurodevelopmental disorder. This gene-disease relationship has been assessed separately.

Autosomal recessive loss of function variants in GRIK2 were first reported in relation to complex neurodevelopmental disorder as early as 2007 (Motazacker et al., PMID: 17847003). The first described variant, a complex null variant (DEL/INV, EX7-11) functionally shown to lead to loss of the protein function, was identified in a consanguineous family with autosomal recessive intellectual disability and no other observed neurological disorders or physical dysmorphism via direct sequencing of probands and some parents and unaffected siblings (PMID: 17847003). A second variant (p.Arg198Ter) [R198X]), predicted to result in nonsense-mediated decay of truncated protein, was identified in 2 homozygous siblings, born to consanguineous parents, who were affected by varying degrees of social and cognitive delay/impairment, epilepsy, dystonia and behavioral disorders (Cordoba et al., PMID: 25039795).

Based on the studies described, GRIK2 variants inherited in an autosomal recessive pattern can result in a loss of function, related to neurodevelopmental disorders such as intellectual disability, social and cognitive delay/impairment, epilepsy, dystonia and behavioral disorders. Based on the volume of evidence in the literature, the genetic evidence was scored 5.5 points.

This gene-disease relationship is also supported by behavioral phenotypes described in 5 studies characterizing global knockout mouse models backcrossed to varying degrees in 129/Sv and/or C57BL/6 lines (PMIDs: 9580260, 15673679, 18332879, 24753134, 11182092), as well as a physiological characterization of a global KO mouse model showing reduced long-term potentiation and impaired short-term synaptic facilitation. A conditional knockout of GRIK2 in adult-born dentate granule cells (abDGCs) in 8-9 week mice resulted in impaired spatial discrimination, increased depolarization of EGABA, and elevated GABAergic synaptic events at 21 dpi, although the relevance to clinical phenotypes is unclear (PMID: 34551304).

In summary, there is moderate evidence to support the relationship between autosomal recessive loss of function variants in GRIK2 and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 10, 2022 (SOP Version 8).