GRIA1

Inheritance Pattern: AD

Disease ID:MONDO:0030964

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030968

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*GRIA1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (de Ligt et al., PMID: 23033978). The condition is characterized by developmental delay/intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder and other behavioral manifestations. Epilepsy has also been reported less frequently. This gene has also been reported in relation to an autosomal recessive intellectual developmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined that there were two distinct disorders with different inheritance patterns and mechanisms. Therefore, the following disease entities have been split into two disease entities, autosomal dominant complex neurodevelopmental disorder (MONDO:0100038) and autosomal recessive complex neurodevelopmental disorder (MONDO:0100038). The autosomal recessive complex neurodevelopmental disorder (MONDO:0100038) has been curated separately. Seven unique missense variants, reported in 12 probands, in 8 publications (PMIDs: 23033978, 28628100, 35675825, 31398340, 35813072, 35982159, 37921875, 35887114) are included in this curation. Two additional unique missense variants were not scored as per GCEP’s decision due to limited testing methodology (PMID: 28628100). Additional individuals have been reported but were not scored due to inclusion of the same proband in more than one publication (PMIDs: 35675825, 30504930, 37921875), possible overlap of published cohorts (PMIDs: 35982159, 25363760), unaffected status (PMID: 35982159), unavailable phenotype (PMID: 37921875), lack of information on the testing method, functional studies not supportive of a deleterious effect of the variant (PMID: 35675825), or benign classification of the variant as concluded by the authors (PMID: 37543562). Both gain- and loss-of-function variants have been reported as the mechanism of pathogenicity, the former effect applying to the recurrent p.Ala636Thr (NM_000827.4:c.1906G>A) variant (PMIDs: 28628100, 35675825). To date, there is no report of affected individuals with heterozygous truncating variants. The parents of a proband, homozygous for a nonsense variant (PMID 35675825) have been reported to be unaffected, per OMIM (Baralle, D. Personal Communication). The present gene-disease relationship is further supported by biochemical evidence. Specifically, AMPA receptors (AMPARs) are homomeric or heteromeric assemblies of four core subunits (GluA1 - 4). *GRIA2* and *GRIA3* encoding the GluA2 and GluA3 subunits respectively, are known to cause developmental disorders with developmental delay, intellectual disability, autistic features and seizures among the reported phenotypes. In summary, there is moderate evidence to support the relationship between *GRIA1* and autosomal dominant complex neurodevelopmental disorder gene-disease relationship. While further 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 GCEP on February 8, 2024 (SOP 10).

Inheritance Pattern: AR

Disease ID:MONDO:0030968

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0030968

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030964

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030964

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*GRIA1* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2022 (Ismail et al., PMID: 35675825). This gene has also been reported in relation to an autosomal dominant Intellectual developmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined that there were two distinct disorders with different inheritance patterns and mechanisms. Therefore, the following disease entities have been split into two disease entities, autosomal dominant complex neurodevelopmental disorder (MONDO:0100038) and autosomal recessive complex neurodevelopmental disorder (MONDO:0100038). The split curation for autosomal dominant complex neurodevelopmental disorder (MONDO:0100038) has been curated separately. A single affected individual with homozygous truncating variants has been reported to date (PMID: 35675825). This individual, born to consanguineous parents, exhibited global developmental delay, with severe intellectual disability and epilepsy. She was non-verbal at the age of 10 years. Behavioral issues included self-injurious behavior and poor sleep. Other features included intermittent divergent strabismus, feeding difficulties, constipation and precocious puberty. Of note, the heterozygous parents of this patient were reported to be unaffected per OMIM (Baralle, D. Personal Communication). The present gene-disease relationship is further supported by biochemical and non-human model organism evidence. Specifically, AMPA receptors (AMPARs) are homomeric or heteromeric assemblies of four core subunits (GluA1 - 4). *GRIA2* and *GRIA3* encoding the GluA2 and GluA3 subunits respectively, are known to cause developmental disorders with developmental delay, intellectual disability, autistic features, and seizures among the reported phenotypes. Knockout of gria1 in X. tropicalis resulted in behavior which was similar to seizures in a small subset of tadpoles, as well as impairment of working memory (PMID: 35675825). In summary, there is limited evidence to support this gene-disease relationship. Although further evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date February 8, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0030968

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia