CUX1

Chr 7AD

cut like homeobox 1

Also known as: CASP, CDP, CDP/Cut, CDP1, COY1, CUTL1, CUX, Clox

NCBI Gene: 1523 ENSG00000257923 UniProt: P39880 OMIM: 116896

CUX1 encodes a transcription factor that controls neuronal differentiation, dendrite development, and synaptogenesis in the brain, particularly in cortical layers II-III. Mutations cause autosomal dominant neurodevelopmental disorder with developmental delay and variable motor or speech delays. The gene is highly constrained against loss-of-function variants, indicating that proper CUX1 function is critical for normal development.

OMIM ResearchSummary from OMIM, UniProt

The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— CUX1

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 7.25

OE 0.08 (0.04–0.16)

Highly constrained

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

Missense Constraint?

3.75Z-score

OE missense 0.64 (0.59–0.69)

543 obs / 850.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.16)

0≤0.351.4

Missense OE?0.64 (0.59–0.69)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 6 / 72.7Missense obs/exp: 543 / 850.7Syn Z: -0.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateCUX1-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.3293th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.16

Literature Evidence

LOFHaploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development.1

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

References