BCL11B

Chr 14AD

BCL11 transcription factor B

ENSG00000127152 UniProt: Q9C0K0 OMIM: 606558

The protein encoded by this gene is a transcriptional repressor containing C2H2-type zinc fingers that regulates gene expression through chromatin remodeling complexes. Mutations cause autosomal dominant intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, as well as severe combined immunodeficiency (SCID). The pathogenic mechanism involves loss of function, leading to disrupted transcriptional regulation critical for both neurodevelopment and T-cell function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.282 OMIM phenotypes

Clinical Summary— BCL11B

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Gene-Disease Validity (ClinGen)

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.28LOEUF

pLI 0.989

Z-score 3.99

OE 0.09 (0.04–0.28)

Highly constrained

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

Missense Constraint

4.71Z-score

OE missense 0.43 (0.39–0.48)

237 obs / 547.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.09 (0.04–0.28)

0≤0.351.4

Missense OE0.43 (0.39–0.48)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 2 / 22.4Missense obs/exp: 237 / 547.2Syn Z: -1.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongBCL11B-related neurodevelopmental disorderLOFAD

0.3594th %ile

GOF

0.2597th %ile

LOF

0.86top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.28

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNThe phenotype of the first de novo monoallelic germ line missense mutation in the BCL11B gene (encoding N441K) strongly implies that the mutant protein acts in a dominant-negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer.PMID:29203643

GOFGiven that the prediction algorithm Zinc Finger Recognition Code (Najafabadi et al., 2015) suggests that both missense mutations are predicted to bind to different alternative genomic sequences (Supplementary Fig. 1B), we hypothesize that the here-identified missense mutation may have comparable ePMID:29985992

LOFTwo additional unrelated patients with a similar disorder carried de novo balanced translocations that interrupted a regulatory domain of the BCL11B gene. These patient cells showed about a 50% decrease in BCL11B mRNA, consistent with haploinsufficiency. The overall findings implicated BCL11B haploiPMID:29985992

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.