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Intellectual disability

Gene: TCF7L2

Amber List (moderate evidence)

TCF7L2 (transcription factor 7 like 2)
EnsemblGeneIds (GRCh38): ENSG00000148737
EnsemblGeneIds (GRCh37): ENSG00000148737
OMIM: 602228, Gene2Phenotype
TCF7L2 is in 2 panels

3 reviews

Konstantinos Varvagiannis (Other)

I don't know

Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.

Consider inclusion in the ID panel with amber/green rating.
Created: 11 Aug 2021, 9:49 p.m. | Last Modified: 11 Aug 2021, 9:49 p.m.
Panel Version: 3.1217

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

Phenotypes
Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system

Publications

Ivone Leong (Genomics England Curator)

Green List (high evidence)

This gene is now associated with a relevant phenotype in Gene2Phenotype (confirmed). There is now enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Created: 6 Oct 2021, 2:25 p.m. | Last Modified: 6 Oct 2021, 2:25 p.m.
Panel Version: 3.1327
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Created: 4 Dec 2020, 3:11 p.m. | Last Modified: 4 Dec 2020, 3:11 p.m.
Panel Version: 3.596

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Additional 11 cases reported.
Created: 9 Sep 2021, 10:44 a.m. | Last Modified: 9 Sep 2021, 10:44 a.m.
Panel Version: 3.1262
A diabetes susceptibility locus associated with common SNVs, see OMIM for details.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo variants (2 frameshift, 6 missense, 1 splice acceptor, 2 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Created: 4 Nov 2020, 9:16 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental disorders

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Developmental disorders
  • Global developmental delay
  • Intellectual disability
  • Autism
  • Attention deficit hyperactivity disorder
  • Myopia
  • Abnormality of skeletal system
Tags
Q4_21_rating
OMIM
602228
Clinvar variants
Variants in TCF7L2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

6 Oct 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag Q4_21_rating tag was added to gene: TCF7L2.

6 Oct 2021, Gel status: 2

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Developmental disorders; Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system

6 Oct 2021, Gel status: 2

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: TCF7L2 were set to 33057194

4 Dec 2020, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).

4 Nov 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: TCF7L2 was added gene: TCF7L2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TCF7L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TCF7L2 were set to 33057194 Phenotypes for gene: TCF7L2 were set to Developmental disorders Review for gene: TCF7L2 was set to AMBER