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Early onset or syndromic epilepsy v1.427 TRRAP Rebecca Foulger commented on gene: TRRAP: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures aren't a prominent feature. Kept rating as Amber.
Early onset or syndromic epilepsy v1.331 TRRAP Rebecca Foulger Source Wessex and West Midlands GLH was added to TRRAP.
Early onset or syndromic epilepsy v1.330 TRRAP Rebecca Foulger Source NHS GMS was added to TRRAP.
Early onset or syndromic epilepsy v1.262 TRRAP Rebecca Foulger edited their review of gene: TRRAP: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.261 TRRAP Helen Lord reviewed gene: TRRAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.258 TRRAP Rebecca Foulger Publications for gene: TRRAP were set to 30827496
Early onset or syndromic epilepsy v1.257 TRRAP Rebecca Foulger Added comment: Comment on phenotypes: MIM:603015 is the gene identifier. Therefore updated OMIM phenotype to the disorder identifier (618454) as per Alison Callaway's review.
Early onset or syndromic epilepsy v1.257 TRRAP Rebecca Foulger Phenotypes for gene: TRRAP were changed from Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 603015; Intellectual disability; Abnormality of the urinary system; Global developmental delay to Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 618454; Intellectual disability; Abnormality of the urinary system; Global developmental delay
Early onset or syndromic epilepsy v1.256 TRRAP Alison Callaway reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 28628100, 30827496; Phenotypes: DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.177 TRRAP Catherine Snow Source Expert Review was added to TRRAP.
Source Expert Review Amber was added to TRRAP.
Added phenotypes Developmental delay with or without dysmorphic facies and autism, 603015 for gene: TRRAP
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.30 TRRAP Konstantinos Varvagiannis gene: TRRAP was added
gene: TRRAP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures
Penetrance for gene: TRRAP were set to unknown
Mode of pathogenicity for gene: TRRAP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TRRAP was set to AMBER
Added comment: Cogné et al. (DDD study among the co-authors - PMID: 30827496) report on 24 individuals with pathogenic TRRAP variants.

17 different variants were reported. All variants were missense SNVs and on most occasions had occurred as de novo or apparently de novo events (paternity and maternity not checked). On one occasion, a parent was not unavailable although the respective grand-parents were not found to harbor the variant. Parental germline mosaicism explained the occurence of a variant in 2 sibs.

The authors suggest a strong genotype-phenotype correlation. Individuals whose variant localized within the residues 1031-1159 (NM_001244580.1) presented with a syndromic form of ID with additional malformations. ID was a universal feature in this group (for those subjects evaluated). For variants outside this cluster of residues the phenotype was rather that of ASD without ID or isolated ID with or without ASD, albeit with some exceptions (eg. F860L also associated with a syndromic presentation). ID was a feature in the majority of individuals belonging to the latter group (67% - all with DD) or overall irrespective of the variant localization (85% for those evaluated - all with DD).

** Epilepsy was a feature in 4 individuals (4/24) belonging to either group. **

All 17 variants were absent from gnomAD with CADD scores supporting a deleterious effect (SIFT/PolyPhen2 (both) predicted a tolerated/benign effect for some eg. Ala1043Thr). A few variants were recurrent, namely Ala1043Thr (5 individuals), Glu1106Lys (2), Gly1883Arg (2), Pro1932Leu (in 2 sibs).

6 further subjects (individuals 25-30, reported separately in the supplement) harbored 6 additional variants with lesser evidence for pathogenicity.

TRRAP is among the 5 most intolerant genes to missense mutations (z-score of 10.1 in ExAC) while it is also intolerant to LoF variants (pLI of 1). No deletions have been reported in DECIPHER and no LoF were identified in the study. Given type of variants and their clustering rather a gain-of-function effect or dominant-negative effect is suggested. As the authors note a LoF effect of non-clustering variants, associated with a milder phenotype cannot excluded. [Mode of pathogenicity to change if thought to be useful].

TRRAP encodes a protein involved in the recruitment to chromatin of histone acetyltransferases. The latter control the process of acetylation of lysine residues in histones and other DNA-binding proteins thus playing a major role in regulation of gene expression. In line with this, RNA sequencing analysis in skin fibroblasts from affected subjects demonstrated dysregulation of expression for several genes implicated in neuronal function and ion transport.

As summarized by the authors: In mice, Trapp knockout is embryonically lethal. Brain-specific knockout leads to premature differentiation of neural progenitors and abnormal brain development. Brain atrophy and microcephaly are observed (microcephaly was a feature in some affected individuals as well, primarily those with variants affecting residues 1031-1159). [PMIDs cited: 11544477, 24792116].

De novo TRRAP variants have been reported also in individuals with neuropsychiatric disorders (PMIDs: 21822266, 23042115, 28392909, 30424743) while TRRAP has been classified among the prenatally-biased genes relevant to its brain expression (PMID:23042115).

A de novo missense variant (c.11270G>A or p.R3757Q) was also previously reported in a study of 264 individuals with epileptic encephalopathy (Epi4K Consortium - PMID: 23934111 - indiv. ND29352).
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TRRAP is not associated with any phenotype in OMIM, nor in G2P.
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As a result, this gene can be considered for inclusion in the epilepsy panel as amber or green.
Sources: Literature