Early onset or syndromic epilepsy
Gene: TRAPPC6B
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
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
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.
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
Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Publications for gene: TRAPPC6B were set to 28626029; 28397838; DOI 10.1055/s-0039-1693664
Publications for gene: TRAPPC6B were set to 28626029; 28397838
Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Source Wessex and West Midlands GLH was added to TRAPPC6B.
Source NHS GMS was added to TRAPPC6B.
Zornitza Stark: Newly described neurodevelopme
Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Publications for gene: TRAPPC6B were set to
Mode of inheritance for gene: TRAPPC6B was changed from to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRAPPC6B were changed from to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862
Expert Review Amber was added to TRAPPC6B. Panel: Genetic Epilepsy Syndromes
TRAPPC6B was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
TRAPPC6B was created by Sarah Leigh