NSDHL

Chr XXLDXLR

NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHL

Also known as: H105E3, SDR31E1, XAP104

NCBI Gene: 50814ENSG00000147383UniProt: Q15738

The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

CHILD syndromeMIM #308050
XLD
CK syndromeMIM #300831
XLR
UniProtCongenital hemidysplasia with ichthyosiform erythroderma and limb defects
366
ClinVar variants
125
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NSDHL
🧬
Gene-Disease Validity (ClinGen)
CK syndrome · XLModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
125 Pathogenic / Likely Pathogenic· 120 VUS of 366 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.29LOEUF
pLI 0.964
Z-score 2.98
OE 0.00 (0.00–0.29)
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.
0.87Z-score
OE missense 0.80 (0.69–0.93)
124 obs / 154.4 exp
Tolerant

Mild missense constraint

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.0.00 (0.00–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.69–0.93)
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.1.16
0≤1.21.6
LoF obs/exp: 0 / 10.3Missense obs/exp: 124 / 154.4Syn Z: -1.02

ClinVar Variant Classifications

366 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic115
Likely Pathogenic10
VUS120
Likely Benign68
Benign34
Conflicting19
115
Pathogenic
10
Likely Pathogenic
120
VUS
68
Likely Benign
34
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
112
0
115
Likely Pathogenic
2
5
3
0
10
VUS
2
81
36
1
120
Likely Benign
0
16
19
33
68
Benign
0
9
14
11
34
Conflicting
—19
Total511318445366

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

View in ClinVar →

Protein Context — Lollipop Plot

NSDHL · protein map & ClinVar variants

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

Gene2Phenotype Curations

NSDHL-related congenital hemidysplasia with ichthyosiform erythroderma and limb defects

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinSkeletal
G2P ↗

NSDHL-related CK syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

CHILD syndrome

MIM #308050

Molecular basis of disorder known

X-linked dominant

CK syndrome

MIM #300831

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — NSDHL
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.
Gabitova-Cornell L et al.·Cancer Cell
2020
Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.
Atzmony L et al.·Pediatr Dermatol
2022
A novel NSDHL variant in CHILD syndrome with gastrointestinal manifestations and localized skin involvement.
Tan EC et al.·Mol Genet Genomic Med
2022
Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report.
Hettiarachchi D et al.·BMC Med Genet
2020Case report
Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review.
Zhuang J et al.·Mol Genet Genomic Med
2023Review
Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome.
König A et al.·Am J Med Genet
2000Review
Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa(1H)/+ mouse.
Cunningham D et al.·Mol Genet Metab
2009Functional
NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis.
Chen M et al.·Breast Cancer Res Treat
2021
NSDHL contributes to breast cancer stem-like cell maintenance and tumor-initiating capacity through TGF-β/Smad signaling pathway in MCF-7 tumor spheroid.
Yoon SH et al.·BMC Cancer
2024
The evolving genetic landscape of ILVEN: A comprehensive review.
Aghajani M et al.·J Eur Acad Dermatol Venereol
2026Review
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools