Early onset or syndromic epilepsy

Gene: TRRAP

I don't know

AD DEDDFA. Complex neurodev disorder apparent from infancy or early childhood. Cogne et al, 2019 (30827496) - 13 unrelated patients (patients 4-16) with global dev delay, variably impaired intellectual development associated with het de novo variants in TRRAP (affecting residues 1031-1159). Only 1 patient had seizures consistent with epileptic encephalopathy. In addition he reported 11 patients (patients 1-3 and 17-24, including 2 sibs 22 & 23) with a somewhat less severe form of the disorder. They all had de novo het mutations in TRRAP outside of the cluster mentioned prev. 4/11 had childhood seizures, mostly absence and tonic clonic. The 2 aff sibs - occured due to mosaicism in the mother. In total 5/24 had seizures.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

I don't know

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.

Created: 25 Nov 2019, 8:21 p.m. | Last Modified: 25 Nov 2019, 8:21 p.m.

Panel Version: 1.427

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.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Comment on phenotypes: MIM:603015 is the gene identifier. Therefore updated OMIM phenotype to the disorder identifier (618454) as per Alison Callaway's review.

Created: 27 Aug 2019, 10:16 a.m. | Last Modified: 27 Aug 2019, 10:16 a.m.

Panel Version: 1.257

Green List (high evidence)

OMIM phenotype has now been listed #618454: DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM. This included epilepsy in one patient, but doesn't appear to be a major part of the phenotype. Additionally PMID 28628100 details two neurodevelopmental disorder cases with variants at codon 1848, but it is unclear whether the patients had epilepsy. Several cases reported by in PMID 30827496, as previously commented on in the reviews below.

Created: 23 Aug 2019, 10:22 a.m. | Last Modified: 23 Aug 2019, 10:22 a.m.

Panel Version: 1.256

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM

Publications

• 28628100
• 30827496

Comment on list classification: Konstantinos Varvagiannis reported on Cogné et al. (PMID: 30827496) who identified 24 individuals with pathogenic TRRAP variants. Different types of seizures starting at different ages (4months - 9 years) have been reported in 4 of the individuals.
TRRAP is in OMIM and it is noted that variable types of seizures affect some patients. It is rated probable in Gene2Phenotype - "TRRAP Disease: Autism and Syndromic Intellectual Disability", although no phenotypes have been assigned to the G2P entry. For both OMIM and G2P it is based on the paper above.
Classifying TRRAP as Amber due to seizures not being found with a majority of affected individuals and awaiting more evidence. Amber rating advised by Genomics England Clinical Team.

Created: 25 Jun 2019, 4:27 p.m. | Last Modified: 22 Jul 2019, 9:34 a.m.

Panel Version: 0.75

I don't know

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

Created: 6 Mar 2019, 2:35 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures

Publications

• 30827496

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments