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Intellectual disability
Gene: GNAI2

GNAI2 (G protein subunit alpha i2)
EnsemblGeneIds (GRCh38): ENSG00000114353
EnsemblGeneIds (GRCh37): ENSG00000114353
OMIM: 139360, Gene2Phenotype
GNAI2 is in 3 panels

4 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Created: 24 Feb 2025, 6:15 p.m. | Last Modified: 24 Feb 2025, 6:15 p.m.

Panel Version: 8.97

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 24 Feb 2025, 6:15 p.m.
Last Modified: 24 Feb 2025, 6:15 p.m.
Panel version: 8.97

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

PMID: 39298586 showed 20 case with "multiorgan dysfunction, with a spectrum of birth defects involving brain, endocrine, skeletal, and other systems. Prominent immune dysregulation resulted from increased infection susceptibility—caused by impaired GPCR signaling for migration of T cells and neutrophils—and life-threatening autoimmunity with T cell hyperresponsiveness." and functional work.
Created: 18 Oct 2024, 12:32 p.m. | Last Modified: 18 Oct 2024, 12:32 p.m.

Panel Version: 7.61

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Immunodefficiency with multisystemic presentation

Publications

PMID: 39298586

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 18 Oct 2024, 12:32 p.m.
Last Modified: 18 Oct 2024, 12:32 p.m.
Panel version: 7.61

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: There is sufficient evidence to promote this to Green at the next GMS panel update. Multiple individuals reported with heterozygous variants supported by functional studies. In PMID:39298586 neurodevelopmental delay in early childhood was reported in 68% of cases, which progressed to ID as patients became older in 53%. Overall patients present with a highly variable phenotype that would be suited to the R27 Paediatic disorders super panel - inclusion on the ID panel would feed into R27.
Created: 15 Nov 2024, 10:16 a.m. | Last Modified: 15 Nov 2024, 10:16 a.m.

Panel Version: 8.34

Ham et al. (2024) (PMID: 39298586) - 20 individuals from 18 unrelated families with heterozygous GOF missense variants in GNAI2 and highly heterogenous clinical presentations. Most commonly observed was disruption of the immune system, with almost 90% of cases exhibiting recurrent, unusual, and/or severe infections. Other features include birth defects, growth abnormalities, neurodevelopmental delay progressing to ID at later stages, brain structural abnormalities and various dysmorphic features. Authors dubbed the syndromic disorder with the acronym MAGIS - Midline malformations of the brain,
Anterior hypopituitarism, Growth retardation, Immunodeficiency/immunodysregulation, Skeletal
abnormalities.
Created: 15 Nov 2024, 10:04 a.m. | Last Modified: 15 Nov 2024, 10:04 a.m.

Panel Version: 8.30

Lecoquierre et al. (2019) (PMID: 31036916) identified a de novo GNAI2 missense variant (p.Arg179His) in a proband with a syndromic developmental disorder. They highlighted that a distinct substitution of the same residue (p.Arg179Cys) had also been reported in the denovo-db database, in a patient with a developmental disorder. However, details regarding the exact phenotype are limited and therefore further characterisation is warranted. No function analysis was undertaken to validate the implication on GNAI2.

Hamada et al. (2017) (PMID: 27787898) reported a de novo heterozygous missense mutation (p.Ala227Val) in an individual with periventricular nodular heterotopia, seizures, and intellectual disability. Function studies in knockdown mice showed delayed radial migration of excitatory neurons during corticogenesis. Mice displayed abnormal social behaviours, altered anxiety, and learning deficits.

Not associated with the phenotype in OMIM or G2P.
Created: 8 Jul 2020, 8:08 a.m. | Last Modified: 8 Jul 2020, 8:08 a.m.

Panel Version: 3.156

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Syndromic developmental disorder

Publications

Created: 8 Jul 2020, 8:08 a.m.
Last Modified: 8 Jul 2020, 8:08 a.m.
Panel version: 8.30

Zornitza Stark (Australian Genomics)

I don't know

Two individuals reported, some functional data.
Sources: Literature
Created: 23 Apr 2020, 4:27 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Syndromic intellectual disability

Publications

Created: 23 Apr 2020, 4:27 a.m.

Panel version: 3.31

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
NHS GMS

Phenotypes

Syndromic intellectual disability

OMIM

139360

Clinvar variants

Variants in GNAI2

Penetrance

None

Publications

Mode of Pathogenicity

Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Panels with this gene

History Filter Activity

25 Feb 2025, Gel status: 3

Removed Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_24_promote_green was removed from gene: GNAI2.

24 Feb 2025, Gel status: 3

Added New Source, Added New Source, Status Update

Sarah Leigh (Genomics England Curator)

Source NHS GMS was added to GNAI2. Source Expert Review Green was added to GNAI2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

15 Nov 2024, Gel status: 2