TBR1

Chr 2AD

T-box brain transcription factor 1

Also known as: AUTS5, IDDAS, TBR-1, TES-56

NCBI Gene: 10716ENSG00000136535UniProt: Q16650

This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with autism and speech delayMIM #606053
AD
353
ClinVar variants
94
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— TBR1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
94 Pathogenic / Likely Pathogenic· 200 VUS of 353 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.19LOEUF
pLI 0.999
Z-score 4.39
OE 0.04 (0.01–0.19)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.64Z-score
OE missense 0.47 (0.41–0.53)
172 obs / 368.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.41–0.53)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 1 / 24.5Missense obs/exp: 172 / 368.4Syn Z: 0.69

ClinVar Variant Classifications

353 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic50
VUS200
Likely Benign44
Benign5
Conflicting5
44
Pathogenic
50
Likely Pathogenic
200
VUS
44
Likely Benign
5
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
7
21
0
44
Likely Pathogenic
17
13
20
0
50
VUS
2
187
10
1
200
Likely Benign
0
14
2
28
44
Benign
0
0
2
3
5
Conflicting
—5
Total352215532348

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TBR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TBR1-related autism

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
T-BOX, BRAIN, 1; TBR1
MIM #604616 · *

Intellectual developmental disorder with autism and speech delay

MIM #606053

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autism spectrum disorder: neuropathology and animal models.
Varghese M et al.·Acta Neuropathol
2017Review
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.
Nambot S et al.·Eur J Hum Genet
2020Review
[Analysis of a child featuring global developmental delay and autism due to variant of TBR1 gene and a literature review].
Liu J et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024Review
Shared and Distinct Functional Effects of Patient-Specific Tbr1 Mutations on Cortical Development.
Co M et al.·J Neurosci
2022Functional
A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.
Okuyama K et al.·Nat Immunol
2024
Novel TBR1 c.1303C>T Variant Led to Diagnosis of Intellectual Developmental Disorder with Autism and Speech Delay: Application of Comprehensive Family-Based Whole-Genome Analysis.
Ćuk M et al.·Genes (Basel)
2025
The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum.
McDermott JH et al.·Eur J Med Genet
2018Case report
A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability.
Sapey-Triomphe LA et al.·Hum Genomics
2020Case report
Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia.
Sperandeo A et al.·Brain
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Proven Pathogenic or Probably Pathogenic TBR1 Variant

A Pilot, Multicentre, Controlled, Open-label Study Evaluating 24 Months of Lithium Carbonate Treatment in Patients With TBR1-related Neurocognitive Disorder

RECRUITING
NCT06776848Phase PHASE1, PHASE2Centre Hospitalier Universitaire DijonStarted 2025-09-12
Observation phaseLithium treatmentbiological monitoring

External Resources

Links to major genomics databases and tools