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Intellectual disability

Gene: GNB5

Green List (high evidence)

GNB5 (G protein subunit beta 5)
EnsemblGeneIds (GRCh38): ENSG00000069966
EnsemblGeneIds (GRCh37): ENSG00000069966
OMIM: 604447, Gene2Phenotype
GNB5 is in 4 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: GNB5 identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.

GNB5 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Concur with Green rating, as sufficient number of individuals and variants for GNB5 to be included on panel. Phenotype is relevant for inclusion and GNB5 is probable in Gene2Phenotype.
Created: 21 May 2019, 10:30 a.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182).

PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described.

The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux).

The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L).

Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one.

As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability.

Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes.

Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out.

Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies.

PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies.

PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing.

PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599.

PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion.

GNB5 is included in diagnostic gene panels for intellectual disability offered by different laboratories.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Created: 19 Nov 2018, 11:26 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182
  • Intellectual developmental disorder with cardiac arrhythmia, 617173
OMIM
604447
Clinvar variants
Variants in GNB5
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to GNB5. Added phenotypes Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Intellectual developmental disorder with cardiac arrhythmia, 617173 for gene: GNB5 Publications for gene GNB5 were changed from 27523599; 27677260; 28697420; 29368331 to 27677260; 28697420; 29368331; 30914295; 27523599 Rating Changed from No List (delete) to Green List (high evidence)

19 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: GNB5 was added gene: GNB5 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331 Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182 Penetrance for gene: GNB5 were set to Complete Review for gene: GNB5 was set to GREEN gene: GNB5 was marked as current diagnostic