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Intellectual disability

Gene: TCF20

Green List (high evidence)

TCF20 (transcription factor 20)
EnsemblGeneIds (GRCh38): ENSG00000100207
EnsemblGeneIds (GRCh37): ENSG00000100207
OMIM: 603107, Gene2Phenotype
TCF20 is in 5 panels

6 reviews

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: Updated as phenotype added to OMIM in May 2019
Created: 27 Jun 2019, 3:28 p.m. | Last Modified: 27 Jun 2019, 3:28 p.m.
Panel Version: 2.901

Rebecca Foulger (Genomics England curator)

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.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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

Zornitza Stark (Australian Genomics)

Green List (high evidence)

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

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

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 : NA
Created: 27 Jul 2017, 8:40 p.m.

Mode of inheritance
Unknown

Publications

Louise Daugherty (Genomics England Curator)

Green List (high evidence)

As a result of watchlist tag audit the watchlist tag was removed from TCF20 this is now a green gene with sufficient evidence/review
Created: 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 mild
Created: 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 gene
Created: 18 Jul 2018, 1 p.m.
added de novo tag and watchlist tag
Created: 18 Jul 2018, 12:59 p.m.
Comment on phenotypes: added phenotype from gene2phenotype
Created: 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.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • TCF20 syndrome
  • Intellectual disability
  • developmental delay
  • Developmental delay with variable intellectual impairment and behavioral abnormalities 618430
Tags
de novo
OMIM
603107
Clinvar variants
Variants in TCF20
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

13 Jan 2020, Gel status: 3

Removed Tag

Louise Daugherty (Genomics England Curator)

Tag watchlist was removed from gene: TCF20.

27 Jun 2019, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

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

13 May 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: tcf20 has been classified as Green List (High Evidence).

13 May 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: TCF20 were changed from TCF20 syndrome; Intellectual disability to TCF20 syndrome; Intellectual disability; developmental delay

13 May 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: TCF20 were set to 27436265; 25533962; 27479843; 28135719

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to TCF20.

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: TCF20 were set to 27436265; 25533962; 27479843; 28135719

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: TCF20 were set to 27436265; 25533962; 27479843, 28135719

18 Jul 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: TCF20 were set to TCF20 syndrome; Intellectual disability

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: TCF20 were set to 27436265; 25533962

18 Jul 2018, Gel status: 2

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: TCF20 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: TCF20 were set to 27436265

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

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.

28 Jul 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

27 Jul 2017, Gel status: 0

Created

BRIDGE consortium (NIHRBR-RD)

TCF20 was created by BRIDGE

27 Jul 2017, Gel status: 0

Added New Source

BRIDGE consortium (NIHRBR-RD)

TCF20 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene