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Early onset or syndromic epilepsy v2.491 TRAPPC12 Sarah Leigh Tag for-review was removed from gene: TRAPPC12.
Early onset or syndromic epilepsy v2.491 TRAPPC12 Sarah Leigh commented on gene: TRAPPC12
Early onset or syndromic epilepsy v2.490 TRAPPC12 Sarah Leigh Source Expert Review Green was added to TRAPPC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.260 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: With addition of the recently reported case, there are now at least 3 unrelated patients with epilepsy and biallelic variants in this gene (PMIDs: 28777934 and 32369837).

This now reaches threshold for inclusion as diagnostic-grade, and therefore TRAPPC12 can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Early onset or syndromic epilepsy v1.497 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger Marked gene: TRAPPC12 as ready
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger commented on gene: TRAPPC12: 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:
Early onset or syndromic epilepsy v1.191 TRAPPC12 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAPPC12.
Early onset or syndromic epilepsy v1.190 TRAPPC12 Rebecca Foulger Source NHS GMS was added to TRAPPC12.
Early onset or syndromic epilepsy v1.189 TRAPPC12 Rebecca Foulger edited their review of gene: TRAPPC12: Added comment: 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. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 TRAPPC12 Tracy Lester reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: ; Publications: 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: Comment on list classification: Kept rating as Amber: 2 literature cases only in PMID:28777934. Seizures are a phenotype of both cases but further cases required for a diagnostic rating.; to: Comment on list classification: Kept rating as Amber: 2 families only in PMID:28777934. Seizures are a phenotype in 2/3 of the patients (one patient from each family).
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports epilepsy in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).; to: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. Epilepsy is reported in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports seizures in all 3 patients.; to: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports epilepsy in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).
Early onset or syndromic epilepsy v0.632 TRAPPC12 Rebecca Foulger Marked gene: TRAPPC12 as ready
Early onset or syndromic epilepsy v0.632 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.632 TRAPPC12 Rebecca Foulger Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.632 TRAPPC12 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: 2 literature cases only in PMID:28777934. Seizures are a phenotype of both cases but further cases required for a diagnostic rating.
Early onset or syndromic epilepsy v0.632 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.631 TRAPPC12 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v0.631 TRAPPC12 Rebecca Foulger Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.631 TRAPPC12 Rebecca Foulger Added comment: Comment on list classification: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports seizures in all 3 patients.
Early onset or syndromic epilepsy v0.631 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.630 TRAPPC12 Rebecca Foulger commented on gene: TRAPPC12
Early onset or syndromic epilepsy v0.630 TRAPPC12 Rebecca Foulger Publications for gene: TRAPPC12 were set to
Early onset or syndromic epilepsy v0.629 TRAPPC12 Rebecca Foulger Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669
Early onset or syndromic epilepsy v0.628 TRAPPC12 Rebecca Foulger Mode of inheritance for gene: TRAPPC12 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy TRAPPC12 Zornitza Stark reviewed gene: TRAPPC12
Early onset or syndromic epilepsy TRAPPC12 Sarah Leigh Added gene to panel