GRIK2

Inheritance Pattern: AR

Disease ID:MONDO:0012614

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0859201

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*GRIK2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2016 (Guzman et al., PMID: 28180184). Clinical features include intellectual disability, developmental and speech delay, motor delay, hypotonia, hypertonia, visual impairment, seizures, abnormal myelination, and autism spectrum disorder. Variants in *GRIK2* have also been reported with autosomal recessive complex neurodevelopmental disorder. This gene-disease relationship has been assessed separately. A pathogenic de novo missense variant in *GRIK2* (c.1969G>A [p.Ala657Thr]) was first identified in a 2016 study by Guzman et al. (PMID: 28180184) via trio whole-exome sequencing of a 10 year-old proband who displayed ataxia, motor and speech delay, and intellectual disability, and her unaffected parents. Subsequently, 5 additional unrelated probands harboring the same variant were described in a 2021 study (Stolz et al., PMID: 34375587) which performed trio whole-exome sequencing on the probands and their parents, including the proband from the 2016 study. In this study, two additional *GRIK2* missense variants (c.1979C>A [p.Thr660Lys] and c.1979C>G [p.Thr660Arg]) were also identified. All three variants were *de novo* missense variants affecting the GluK2a protein M3 domain which forms the ion channel pore, were found in multiple unrelated heterozygous probands via trio whole-exome sequencing of the probands and their parents, and each proband displayed several neurodevelopmental symptoms such as intellectual disability, developmental and speech delay, motor delay, hypotonia, hypertonia, visual impairment, seizures, abnormal myelination, and autism spectrum disorder. Electrophysiological experiments performed in cell culture as part of the 2021 study demonstrated complex effects on functional properties and membrane localization of homomeric and heteromeric KARs, in particular, markedly slowed gating kinetics, thus supporting the clinical phenotypes observed in the probands. An additional variant, c.2003T>C [p.Ile668Thr], with a similar autosomal dominant inheritance pattern and gain of function molecular mechanism was identified in one proband via identical methods, and also described in the 2021 study (PMID: 34375587). However, compared to the other three variants, this variant affects a different protein domain (M3-S2 linker), the proband only had autism spectrum disorder, and electrophysiological molecular experiments displayed a milder phenotype. Therefore, we did not include the c.2003T>C [p.Ile668Thr] in the scoring for this curation. Based on the studies described, *GRIK2* variants affecting the M3 protein domain result in a gain of function inherited in an autosomal dominant pattern, and are associated with a spectrum of neurodevelopmental disorders. Based on the volume of evidence in the literature, the maximum score for genetic evidence (12 points) has been reached. In summary, there is definitive evidence to support the relationship between autosomal dominant gain of function missense variants in the *GRIK2* M3 domain 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).

Inheritance Pattern: AD

Disease ID:MONDO:0859201

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012614

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*GRIK2* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2007 (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. To date, only two families have been reported. The first described variant, a complex null variant (DEL/INV, EX7-11) functionally shown to lead to loss of function, was identified in a consanguineous family with autosomal recessive intellectual disability and no other observed neurological disorders or physical dysmorphism (Motazacker et al., PMID: 17847003). A second variant (p.Arg198Ter), predicted to result in nonsense-mediated decay of the 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). The mechanism of pathogenicity is reported to be biallelic loss of function. 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 knockout mouse model showing reduced long-term potentiation and impaired short-term synaptic facilitation. A conditional knockout of *Grik2* in adult-born dentate granule cells in 8-9 week old mice resulted in impaired spatial discrimination, increased depolarization of EGABA, and elevated GABAergic synaptic events at 21 dpi (PMID: 34551304), although the relevance to clinical phenotypes is unclear. In summary, there is moderate evidence to support the relationship between *GRIK2* and autosomal recessive complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 10, 2022 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0012614

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012614

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0859201

Submitter: Labcorp Genetics (formerly Invitae)