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Genetic epilepsy syndromes

Gene: TRAPPC6B

Amber List (moderate evidence)

TRAPPC6B (trafficking protein particle complex 6B)
EnsemblGeneIds (GRCh38): ENSG00000182400
EnsemblGeneIds (GRCh37): ENSG00000182400
OMIM: 610397, Gene2Phenotype
TRAPPC6B is in 2 panels

4 reviews

Konstantinos Varvagiannis (Other)

I don't know

Seizures (of GTC type) have been described in 6 individuals (Marin-Valencia et al. 2018 - PMID: 28626029). Subsequent studies did not report this feature in affected individuals.

[Review below of relevant studies, for the ID panel]

9 individuals from 5 families have been reported, all harboring loss-of-function variants in homozygous state.
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Marin-Valencia et al. (2018 - PMID: 28626029) describe 6 individuals from 3 consanguineous families - all from Egypt - homozygous for a specific splicing variant. Features incl. global DD and ID (6/6), seizures (6/6 - GTC), microcephaly. Some presented with extrapyramidal symptoms. TRAPPC6B is expressed in the fetal brain and the adult brain and spinal cord. The splicing variant affected the splice-donor site in both protein coding transcripts [NM_001079537.2 (the predominant transcript) and NM_177452.3 | in both : c.150-2A>G) and skipping of exon 2 was shown upon RT-PCR in patient fibroblasts.

The variant - probably a founder mutation - has an AF of 0.00004991 in gnomAD (possibly 0.0023 in Egyptians) and was found following WES, with a linkage peak with a MPT pLOD score > 2 in 2 families.

The transport protein particle (TRAPP) is a multisubunit protein complex regulating mebrane trafficking from the ER to the Golgi and plasma membrane. The different TRAPP complexes (I,II,III) comprise different subunits apart from the 7 core ones.

Patient fibroblasts did not show obvious differences in the ER/Golgi morphology or defects in trafficking.

Mutations in genes for other subunits cause disorders with neurological manifestations and/or - in the case of TRAPPC9 - intellectual disability.

Zebrafish studies were carried out. In zebrafish trappc6b transcript is detected in the CNS early (24 hpf). Morpholino knockdown led to decreased survival, reduced head size despite normal body length (similar the microcephaly phenotype) with increase in apoptotic cells (which might be compatible with the course in few individuals) and neuronal hyperexcitability with lowered seizure threshold (seizures reported in 6/6 patients).
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Harripaul et al. (2018 - PMID: 28397838) identified 2 individuals from a consanguineous family (from cohort of 192 consanguineous families with ID from Pakistan/Iran investigated by WES). Similarly to the previous report, both subjects were homozygous for a LoF variant (NM_177452.4:c.124C>T or p.Arg42Ter). Sanger confirmation and segregation studies were carried out. The authors do not provide additional information or functional evidence.
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Nair et al. (2019 - DOI: 10.1055/s-0039-1693664) report on a boy born to consanguineous Lebanese parents, homozygous for a stopgain variant (NM_001079537.2:c.23T>A or p.Leu8*). Features included DD and ID, microcephaly, MRI findings of thin corpus callosum and periventricular leucomalacia (thin corpus callosum was also reported in the first study with cortical/cerebellar atrophy in some). The mother was heterozygous for the variant.
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Biallelic TRAPPC6B mutations cause Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy (MIM 617862) with severe ID among the clinical features.
TRAPPC6B is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, Victorian Clinical Genetics, Utrecht UMC, GeneDx etc). The gene is not associated with any phenotype in G2P.
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As a result this gene could possibly be considered for upgrade to green (5 families although in 3 due to a founder mutation, biallelic LoF in all affected individuals, RNA studies for the splicing variant, some suggestive features in zebrafish model, neurological manifestations/ID as part of other TRAPP complex related disorders) or remain amber pending further evidence (clinical details, defect at the cell level).
Created: 25 Aug 2019, 7:39 p.m. | Last Modified: 25 Aug 2019, 7:39 p.m.
Panel Version: 1.256

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

Limited evidence: PMID 28626029 and 28397838 identified 8 patients from 4 consanguinous families with features that include microcephaly, epilepsy and brain atrophy.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862

Publications

Rebecca Foulger (Genomics England curator)

I don't know

The Amber review by Konstantinos Varvagiannis (25 Aug 2019) agrees with the current Amber rating of TRAPPC6B: therefore no further curation required.
Created: 9 Sep 2019, 11:28 a.m. | Last Modified: 9 Sep 2019, 11:28 a.m.
Panel Version: 1.324
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 this gene can remain as Amber.
Created: 15 Aug 2019, 8:11 a.m. | Last Modified: 15 Aug 2019, 8:11 a.m.
Panel Version: 1.223
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Kept rating as Amber: A founder TRAPPC6B variant was reported in recent PMID:28626029 in Egyptian patients with seizures. Plus additional variant in ID patient from PMID:28397838. Further unrelated cases are required for a diagnostic rating.
Created: 8 Nov 2018, 9:36 a.m.
In 2 patients from a consanguineous family, PMID:28397838 (Harripaul et al. 2018) identified a homozygous truncating variant in TRAPPC6N. The patients were selected for non-syndromic ID, which often presents with epilepsy .
Created: 8 Nov 2018, 9:32 a.m. | Last Modified: 4 Jul 2019, 10:52 a.m.
Panel Version: 1.109
In 6 patients from 3 consanguineous Egyptian families with MIM:617862, Marin-Valencia et al. (2018, PMID:28626029) identified a homozygous splice site mutation (c.82-2A-G, NM_177452) in intron 2 of the TRAPPC6B gene. Haplotype analysis suggests a common founder variant. Seizures were reported in 5 patients. In a zebrafish model, the authors show that trappc6b disruption lowers seizure threshold.
Created: 8 Nov 2018, 9:31 a.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Newly described neurodevelopmental disorder, seizures are part of the phenotype.
Created: 22 Aug 2018, 6:46 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM#617862

Publications

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Wessex and West Midlands GLH
  • NHS GMS
  • Victorian Clinical Genetics Services
Phenotypes
  • Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862
OMIM
610397
Clinvar variants
Variants in TRAPPC6B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

9 Sep 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: TRAPPC6B were set to 28626029; 28397838

15 Aug 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: trappc6b has been classified as Amber List (Moderate Evidence).

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to TRAPPC6B.

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to TRAPPC6B.

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Newly described neurodevelopme

8 Nov 2018, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: trappc6b has been classified as Amber List (Moderate Evidence).

8 Nov 2018, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: trappc6b has been classified as Amber List (Moderate Evidence).

8 Nov 2018, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: TRAPPC6B were set to

8 Nov 2018, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: TRAPPC6B was changed from to BIALLELIC, autosomal or pseudoautosomal

8 Nov 2018, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: TRAPPC6B were changed from to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to TRAPPC6B. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

TRAPPC6B was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

TRAPPC6B was created by Sarah Leigh