NHS

Chr XXLDX-linked

NHS actin remodeling regulator

Also known as: CTRCT40, CXN

NCBI Gene: 4810 ENSG00000188158 UniProt: Q6T4R5 OMIM: 302350

The NHS protein regulates actin remodeling and cell morphology, and controls development of the eye, teeth, brain, and craniofacial structures. Mutations cause Nance-Horan syndrome and X-linked cataract, both following X-linked inheritance patterns. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.087), indicating that mutations typically have significant developmental consequences.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing four conserved nuclear localization signals. The encoded protein functions in eye, tooth, craniofacial and brain development, and it can regulate actin remodeling and cell morphology. Mutations in this gene have been shown to cause Nance-Horan syndrome, and also X-linked cataract-40. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLD/X-linkedLOEUF 0.093 OMIM phenotypes

Clinical Summary— NHS

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Gene-Disease Validity (ClinGen)

Nance-Horan syndrome · XLDefinitive

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 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.42

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.82Z-score

OE missense 0.79 (0.74–0.86)

495 obs / 623.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.79 (0.74–0.86)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 34.1Missense obs/exp: 495 / 623.0Syn Z: 1.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNHS-related Nance-Horan syndromeLOFXLR

This gene — mechanism propensity

0.2299th %ile

GOF

0.3689th %ile

LOF

0.86top 5%

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

LOFprediction above median · LOEUF 0.09 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NHS · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Carcinoma, Non-Small-Cell LungNeoplasm Metastasis

A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer

RECRUITING

NCT06119581Phase PHASE3Eli Lilly and CompanyStarted 2023-12-21

LY3537982PembrolizumabPlacebo

Malaria

Trajectories and Mechanisms of Recovery From Malaria: An Observational Study

ACTIVE NOT RECRUITING

NCT05149157Imperial College LondonStarted 2022-08-02

Symptomatic malaria

Hemophilia A

Study to Evaluate the Efficacy and Safety of PF-07055480 / Giroctocogene Fitelparvovec Gene Therapy in Moderately Severe to Severe Hemophilia A Adults

ACTIVE NOT RECRUITING

NCT04370054Phase PHASE3PfizerStarted 2020-08-18

PF-07055480 (giroctocogene fitelparovec): Recombinant AAV2/6 Human Factor VIII Gene Therapy

Knee Osteoarthritis

Dietary Supplementation With Blueberry in OA

ACTIVE NOT RECRUITING

NCT05784545Phase NAUniversity of ExeterStarted 2023-05-22

Blueberry powder supplementMaltodextrin supplementation

Leukemia, Myeloid, Acute

A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)

RECRUITING

NCT06852222Phase PHASE3Janssen Research & Development, LLCStarted 2025-06-04