Submission Details

GNB1 was first reported in relation to autosomal dominant GNB1-related neurodevelopmental disorder (also known as autosomal dominant intellectual disability 42 or GNB1 encephalopathy) in 2016 (Petrovski et al., PMID: 27108799). GNB1 encodes a β subunit of the heterotrimeric G protein complex, which functions as a signal transducer for G-protein coupled receptors and is involved in numerous signaling pathways (PMID: 18488142). The disorder is characterized by global developmental delay, moderate-to-severe intellectual disability, delayed or absent speech, hypotonia, seizures, abnormal vision, and structural brain abnormalities. Other less common findings include dystonia, behavior problems, growth delay, craniofacial defects, and genitourinary abnormalities in males.

Twenty-five unique missense variants that have been reported in 31 probands in 6 publications (PMIDs: 27108799, 27668284, 27759915, 28087732, 29174093, 30194818) are included in this curation. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The majority of reported missense variants are found in exons 6 and 7 of the GNB1 gene, in regions critical for protein interaction, and occur de novo (PMID: 18488142). The most common variant reported to date, p.Ile80Thr, has been identified in at least 13 individuals (PMIDs: 27108799, 30194818, 31735425, 37453880).

The mechanism of pathogenicity is currently unclear but functional analyses of multiple missense variants supports loss of function of the G-protein complex via deficits in dimer formation, heterotrimer assembly, or receptor-driven activation (PMIDs: 28087732, 34522861, 37275776). Variants may have additional loss- or gain-of-function effects on downstream signaling, as demonstrated by the K78R and I80T/N variants, which show gain-of-function (K78R) and loss-of-function (I80T/N) effects on G protein-coupled potassium (GIRK) channel activation (PMIDs: 34522861, 37275776).

At least 7 truncating variants (frameshift, splice site and nonsense) have been reported to date in individuals with neurodevelopmental disorders (PMIDs: 28087732, 32345733, 32918542). GNB1 is highly intolerant to loss-of-function variation (pLI = 1, gnomAD v2.1.1) and to missense variation (Z score = 3.83). However, it is currently unclear whether haploinsufficiency is a mechanism of disease and therefore, these variants were not included in this curation. Additional evidence is needed to clarify the implication of truncating variants in this disorder.

This gene-disease relationship is also supported by a mouse model of the K78R variant which showed developmental delay, spatial learning and memory deficits, seizures and abnormal neuronal excitability (PMIDs: 36405774, 37275776). Of note, Gnb1 haploinsufficient mice did not display enhanced seizure susceptibility (PMID: 37275776).

In summary, there is definitive evidence supporting the relationship between GNB1 and autosomal dominant GNB1-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 16, 2023 (SOP Version 9).

GNB1 was first reported in relation to autosomal dominant GNB1-related neurodevelopmental disorder (also known as autosomal dominant intellectual disability 42 or GNB1 encephalopathy) in 2016 (Petrovski et al., PMID: 27108799). GNB1 encodes a β subunit of the heterotrimeric G protein complex, which functions as a signal transducer for G-protein coupled receptors and is involved in numerous signaling pathways (PMID: 18488142). The disorder is characterized by global developmental delay, moderate-to-severe intellectual disability, delayed or absent speech, hypotonia, seizures, abnormal vision, and structural brain abnormalities. Other less common findings include dystonia, behavior problems, growth delay, craniofacial defects, and genitourinary abnormalities in males.

Twenty-five unique missense variants that have been reported in 31 probands in 6 publications (PMIDs: 27108799, 27668284, 27759915, 28087732, 29174093, 30194818) are included in this curation. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The majority of reported missense variants are found in exons 6 and 7 of the GNB1 gene, in regions critical for protein interaction, and occur de novo (PMID: 18488142). The most common variant reported to date, p.Ile80Thr, has been identified in at least 13 individuals (PMIDs: 27108799, 30194818, 31735425, 37453880).

The mechanism of pathogenicity is currently unclear but functional analyses of multiple missense variants supports loss of function of the G-protein complex via deficits in dimer formation, heterotrimer assembly, or receptor-driven activation (PMIDs: 28087732, 34522861, 37275776). Variants may have additional loss- or gain-of-function effects on downstream signaling, as demonstrated by the K78R and I80T/N variants, which show gain-of-function (K78R) and loss-of-function (I80T/N) effects on G protein-coupled potassium (GIRK) channel activation (PMIDs: 34522861, 37275776).

At least 7 truncating variants (frameshift, splice site and nonsense) have been reported to date in individuals with neurodevelopmental disorders (PMIDs: 28087732, 32345733, 32918542). GNB1 is highly intolerant to loss-of-function variation (pLI = 1, gnomAD v2.1.1) and to missense variation (Z score = 3.83). However, it is currently unclear whether haploinsufficiency is a mechanism of disease and therefore, these variants were not included in this curation. Additional evidence is needed to clarify the implication of truncating variants in this disorder.

This gene-disease relationship is also supported by a mouse model of the K78R variant which showed developmental delay, spatial learning and memory deficits, seizures and abnormal neuronal excitability (PMIDs: 36405774, 37275776). Of note, Gnb1 haploinsufficient mice did not display enhanced seizure susceptibility (PMID: 37275776).

In summary, there is definitive evidence supporting the relationship between GNB1 and autosomal dominant GNB1-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 16, 2023 (SOP Version 9).