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Early onset or syndromic epilepsy v2.478 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; early infantile epileptic encephalopathy (EIEE) to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger Marked gene: GNB5 as ready
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger commented on gene: GNB5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.
Early onset or syndromic epilepsy v1.191 GNB5 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNB5.
Early onset or syndromic epilepsy v1.190 GNB5 Rebecca Foulger Source NHS GMS was added to GNB5.
Early onset or syndromic epilepsy v1.189 GNB5 Rebecca Foulger reviewed gene: GNB5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 GNB5 Tracy Lester reviewed gene: GNB5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Intellectual developmental disorder with cardiac arrhythmia, 617173, Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.110 GNB5 Rebecca Foulger Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182 to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; early infantile epileptic encephalopathy (EIEE)
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Marked gene: GNB5 as ready
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. Sufficient variants and unrelated cases for this gene to be rated green.
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Classified gene: GNB5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Added comment: Comment on list classification: Based on cited literature and review by Konstantinos Varvagiannis.
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1167 GNB5 Sarah Leigh Classified gene: GNB5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1167 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.927 GNB5 Konstantinos Varvagiannis gene: GNB5 was added
gene: GNB5 was added to Genetic epilepsy syndromes. 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
Added comment: 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.

Epilepsy was a feature in at least 6 individuals reported.

As a result this gene can be considered for inclusion in this panel as green or amber.
Sources: Literature, Expert Review