Intellectual disability - microarray and sequencing
Gene: TCF20Comment on phenotypes: Updated as phenotype added to OMIM in May 2019Created: 27 Jun 2019, 3:28 p.m. | Last Modified: 27 Jun 2019, 3:28 p.m.
Panel Version: 2.901
Comment on list classification: Updated rating from Amber to Green following recent external review by Konstantinos Varvagiannis (Dec 2018 and Feb 2019). The Torti et al., 2019 article (PMID:30739909) describes 27 individuals from 24 families with novel TCF20 variants. All 27 individuals had developmental delay/intellectual disability (DD/ID). Together with the individual in PMID:30525188 (Snoeijen-Schouwenaars et al 2019, Supplementary Table 2) and the additional evidence listed by Konstantinos Varvagiannis, these papers provide additional cases since the Amber rating in July 2018, and support that ID is a consistent feature amongst TCF20 patients.Created: 13 May 2019, 1:29 p.m.
PMID: 30739909 (Torti et al. 2019) provides information on 27 new individuals and compares with the phenotype of 17 previously reported ones. DD/ID was an almost universal feature (27/27 or 43/44 when considering all previously published cases).Created: 14 Feb 2019, 5:14 p.m.
One further individual investigated for mild ID and focal epilepsy was found to harbor a de novo frameshift variant [NM_005650.3:c.5430dup or p.(Ala1811Serfs*4)] in PMID: 30525188.Created: 19 Dec 2018, 11:07 a.m.
Apart from the 2 unrelated individuals with ID and de novo LoF variants reported by Schäfgen et al. (PMID: 27436265), 3 further relevant patients were reported by Babbs et al. (PMID: 25228304).
In the latter article, 2 sibs had disruption of TCF20 secondary to a translocation. One presented with borderline intellectual functioning (IQ of 79), while the other had mild to moderate intellectual disability. Both were presumed to have this chromosomal translocation due to parental germline mosaicism. None of the parents presented with ID.
In addition a third individual from the same study harbored a de novo frameshift variant and was reported to have moderate intellectual disability.
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In Decipher 23 patients have been reported with TCF20 mutations, 14 of whom as pathogenic/likely pathogenic. Developmental delay (speech/motor/global) was specifically recorded as a feature in 15 and intellectual disability in 4 (2 mild - 2 moderate). [Only 7 individuals from this list seem to have been included in the DDD study - details below]
https://decipher.sanger.ac.uk/gene/TCF20#variants/TCF20/patient-overlap/snvs
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Many of the individuals with de novo mutations from large patient cohorts (discussed in previous TCF20 review here) are listed in the denovo-db when filtering for coding variants:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=tcf20
[This list includes 7 patients from the DDD study (PMID: 28135719) who also appear in Decipher, as well as those reported in a meta-analysis by Lelieveld et al (PMID: 27479843)].
Additional reports from large patient cohorts exist:
- Vissers et al. (PMID: 28333917) report on an individual with de novo frameshift variant [Patient 66 - table 1 - NM_005650.1:c.3889_3890insT or p.(Asn1297fs) - phenotype of "psychomotor retardation" in suppl.]
- Bowling et al. (PMID: 28554332) report on an additional patient with de novo LoF variant and relevant phenotype [Indiv. ID : 00078-C - NM_005650.3:c.5385_5386delTG or (p.Cys1795Trpfs) - phenotype of moderate ID, ASD and Speech delay]
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TCF20 is not associated with any phenotype in OMIM.
In G2P this gene is included in the DD panel, associated with TCF20 syndrome.
TCF20 is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc)
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As a result, this gene could be considered for upgrade to green.Created: 18 Dec 2018, 1:14 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Variants in this GENE are reported as part of current diagnostic practice
Please also note multiple submissions in ClinVar from clinical laboratories.Created: 21 Jun 2018, 12:40 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Variants in this GENE are reported as part of current diagnostic practice
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NACreated: 27 Jul 2017, 8:40 p.m.
Mode of inheritance
Unknown
Publications
As a result of watchlist tag audit the watchlist tag was removed from TCF20 this is now a green gene with sufficient evidence/reviewCreated: 13 Jan 2020, 4:17 p.m. | Last Modified: 13 Jan 2020, 4:17 p.m.
Panel Version: 3.0
After internal clinical review it was agreed this gene should be Amber on this panel, based upon the two cases, albeit borderline, as the ID is described as mildCreated: 24 Jul 2018, 9:42 a.m.
Apart from this paper https://www.ncbi.nlm.nih.gov/pubmed/27436265 the other publications are all meta/large scale analyses https://www.ncbi.nlm.nih.gov/pubmed/27479843; https://www.ncbi.nlm.nih.gov/pubmed/25533962
The clinvar cases https://www.ncbi.nlm.nih.gov/clinvar/?term=tcf20%5Bgene%5D noted by expert review although Clinical Significance in Clinvar defined as pathogenic, there is no phenotype info other than " Inborn genetic diseases" (phenotype absent from OMIM), so I am not sure this can be used bonafide evinced that variaints cause ID.There are also many cases listed in DDD https://decipher.sanger.ac.uk/search?q=tcf20#consented-patients/results but the contribution to phenotype is denoted as not confirmed. TCF20 is on the VCGS BRIDGE SPEED (NIHRRD-BR) panels, but should be noted evidence is lower than ours eg: 2 cases. Past onto internal clinical team for further review and consideration.Created: 18 Jul 2018, 1:59 p.m.
Comment on publications: Added publications suggested from external expert review to support upgrading of the geneCreated: 18 Jul 2018, 1 p.m.
added de novo tag and watchlist tagCreated: 18 Jul 2018, 12:59 p.m.
Comment on phenotypes: added phenotype from gene2phenotypeCreated: 18 Jul 2018, 12:56 p.m.
Comment on publications: added publication PMID: 27436265 that describes two individuals with de novo TCF20 sequence variants identified in a cohort of 313 individuals with intellectual disability of unknown aetiology. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband.Created: 18 Jul 2018, 12:15 p.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.Created: 28 Jul 2017, 4:45 p.m.
Tag watchlist was removed from gene: TCF20.
Phenotypes for gene: TCF20 were changed from TCF20 syndrome; Intellectual disability; developmental delay to TCF20 syndrome; Intellectual disability; developmental delay; Developmental delay with variable intellectual impairment and behavioral abnormalities 618430
Gene: tcf20 has been classified as Green List (High Evidence).
Phenotypes for gene: TCF20 were changed from TCF20 syndrome; Intellectual disability to TCF20 syndrome; Intellectual disability; developmental delay
Publications for gene: TCF20 were set to 27436265; 25533962; 27479843; 28135719
Source Victorian Clinical Genetics Services was added to TCF20.
Publications for gene: TCF20 were set to 27436265; 25533962; 27479843; 28135719
Publications for gene: TCF20 were set to 27436265; 25533962; 27479843, 28135719
Phenotypes for gene: TCF20 were set to TCF20 syndrome; Intellectual disability
Publications for gene: TCF20 were set to 27436265; 25533962
Mode of inheritance for gene: TCF20 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF20 were set to 27436265
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
This gene has been classified as Amber List (Moderate Evidence).
TCF20 was created by BRIDGE
TCF20 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene