DHCR7

Chr 11

7-dehydrocholesterol reductase

Also known as: SLOS

NCBI Gene: 1717 ENSG00000172893 UniProt: Q9UBM7

DHCR7 encodes an oxidoreductase that catalyzes the final step of cholesterol biosynthesis, converting 7-dehydrocholesterol to cholesterol. Mutations cause Smith-Lemli-Opitz syndrome, an autosomal recessive disorder characterized by intellectual disability, distinctive facial features, syndactyly of the second and third toes, and in severe cases holoprosencephaly, with phenotypic severity ranging from minimal abnormalities with near-normal intelligence to profound developmental delays. The gene shows very low tolerance to loss-of-function variants (pLI near zero), reflecting the critical importance of cholesterol synthesis for normal development.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.35

Clinical Summary— DHCR7

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Gene-Disease Validity (ClinGen)

Smith-Lemli-Opitz syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

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

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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?

1.35LOEUF

pLI 0.000

Z-score 0.31

OE 0.93 (0.65–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.45Z-score

OE missense 1.07 (0.98–1.18)

322 obs / 300.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.93 (0.65–1.35)

0≤0.351.4

Missense OE?1.07 (0.98–1.18)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 20 / 21.5Missense obs/exp: 322 / 300.0Syn Z: -1.88

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDHCR7-related Smith-Lemli-Opitz syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6259th %ile

GOF

0.6639th %ile

LOF

0.3455th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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