BHLHE23

Chr 20

basic helix-loop-helix family member e23

Also known as: BETA4, BHLHB4, Beta3b, bA305P22.3

NCBI Gene: 128408 ENSG00000125533 UniProt: Q8NDY6

This gene encodes a basic helix-loop-helix transcription factor that functions as a transcriptional repressor and modulates gene expression required for pancreatic and neuronal cell differentiation and maintenance, with particular importance for rod bipolar cell maturation in the retina. Mutations cause autosomal recessive retinal dystrophy with early childhood onset, affecting primarily the visual system. The gene shows moderate tolerance to loss-of-function variants, consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the basic helix-loop-helix transcription factor family. Members of this family contain two highly conserved and functionally distinct domains: the basic domain targets sequence-specific DNA binding, while the helix-loop-helix domain facilitates protein interaction. Studies of a related gene in mouse suggest that the encoded protein may function as a transcriptional repressor in the pancreas and brain, and that it is required for normal retinal function. [provided by RefSeq, May 2013]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.55

Clinical Summary— BHLHE23

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Population Constraint (gnomAD)

Low constraint (pLI 0.20) — loss-of-function variants are relatively tolerated in the population.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.55LOEUF

pLI 0.196

Z-score 0.97

OE 0.37 (0.13–1.55)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.13Z-score

OE missense 1.04 (0.87–1.24)

86 obs / 82.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.37 (0.13–1.55)

0≤0.351.4

Missense OE?1.04 (0.87–1.24)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 1 / 2.7Missense obs/exp: 86 / 82.7Syn Z: -1.40

This gene — mechanism propensity

0.6261th %ile

GOF

0.4184th %ile

LOF

0.59top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.