Smith-Lemli-Opitz syndrome

Summary

Smith-Lemli-Opitz syndrome (MONDO:0010035) is a disease caused by DHCR7 (GenCC Definitive), with 4 cohort genes and 16 clinical trials. Top therapeutic interventions include simvastatin, cholic acid, and lovastatin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: DHCR7 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,037
• Phenotypes (HPO): 106
• Clinical trials: 16

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3.7	Europe	Validated
Annual incidence	1-9 / 100 000	1.4314	Korea, Republic of	Validated
Prevalence at birth	1-9 / 100 000	1.7	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	5.85	Slovakia	Validated
Prevalence at birth	1-5 / 10 000		Czech Republic	Validated
Prevalence at birth	1-9 / 100 000	2.6	Canada	Not yet validated
Prevalence at birth	1-9 / 100 000	2.65	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

106 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004691	2-3 toe syndactyly	Very frequent (80-99%)
HP:0006482	Abnormal dental morphology	Very frequent (80-99%)
HP:0007477	Abnormal dermatoglyphics	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0010569	Elevated 7-dehydrocholesterol	Very frequent (80-99%)
HP:0010880	Increased nuchal translucency	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Frequent (30-79%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000212	Gingival overgrowth	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0000965	Cutis marmorata	Frequent (30-79%)
HP:0000992	Cutaneous photosensitivity	Frequent (30-79%)
HP:0000996	Facial capillary hemangioma	Frequent (30-79%)
HP:0001162	Postaxial hand polydactyly	Frequent (30-79%)
HP:0001262	Excessive daytime somnolence	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001600	Abnormality of the larynx	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001830	Postaxial foot polydactyly	Frequent (30-79%)
HP:0002089	Pulmonary hypoplasia	Frequent (30-79%)
HP:0002101	Abnormal lung lobation	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002777	Tracheal stenosis	Frequent (30-79%)
HP:0002827	Hip dislocation	Frequent (30-79%)
HP:0004422	Biparietal narrowing	Frequent (30-79%)
HP:0005916	Abnormal metacarpal morphology	Frequent (30-79%)
HP:0006610	Wide intermamillary distance	Frequent (30-79%)
HP:0006695	Atrioventricular canal defect	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Smith-Lemli-Opitz syndrome
Mondo ID	MONDO:0010035
MeSH	D019082
OMIM	270400
Orphanet	818
DOID	DOID:14692
ICD-10-CM	E78.72
ICD-11	1231469858
NCIT	C85071
SNOMED CT	43929004
UMLS	C0175694
MedGen	61231
GARD	0005683
NORD	1724
Is cancer (heuristic)	no

Also known as: 7-dehydrocholesterol reductase deficiency · polydactyly, sex reversal, renal hypoplasia, and unilobular lung · RSH syndrome · Rutledge lethal multiple congenital anomaly syndrome · SLO syndrome · SLOS · Smith Lemli Opitz syndrome · Smith-Lemli-Opitz syndrome

Data availability: 1,037 ClinVar variants · 6 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Smith-Lemli-Opitz syndrome

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

292 likely benign, 99 uncertain significance, 60 likely pathogenic, 50 conflicting classifications of pathogenicity, 40 pathogenic, 39 pathogenic/likely pathogenic, 15 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
279778	NM_000083.3(CLCN1):c.1437_1450del (p.Pro480fs)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280100	NM_000083.3(CLCN1):c.854G>A (p.Gly285Glu)	CLCN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071907	NM_001360.3(DHCR7):c.1328G>C (p.Arg443Pro)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073442	NC_000011.9:g.(?71146411)(71146895_?)del	DHCR7	Pathogenic	criteria provided, single submitter
1074358	NM_001360.3(DHCR7):c.545G>A (p.Trp182Ter)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076413	NM_001360.3(DHCR7):c.600C>G (p.Tyr200Ter)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076651	NM_001360.3(DHCR7):c.1295A>G (p.Tyr432Cys)	DHCR7	Pathogenic	criteria provided, multiple submitters, no conflicts
1342621	NM_001360.3(DHCR7):c.744G>A (p.Trp248Ter)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361572	NM_001360.3(DHCR7):c.949del (p.Leu317fs)	DHCR7	Pathogenic	criteria provided, single submitter
1383040	NM_001360.3(DHCR7):c.969_970del (p.Tyr324fs)	DHCR7	Pathogenic	criteria provided, single submitter
1392687	NM_001360.3(DHCR7):c.1360A>T (p.Lys454Ter)	DHCR7	Pathogenic	criteria provided, single submitter
1414460	NM_001360.3(DHCR7):c.644_659del (p.Asn214_Phe215insTer)	DHCR7	Pathogenic	criteria provided, single submitter
1441328	NC_000011.9:g.(?71146411)(71156008_?)del	DHCR7	Pathogenic	criteria provided, single submitter
1452130	NM_001360.3(DHCR7):c.634del (p.Thr212fs)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455236	NM_001360.3(DHCR7):c.1220A>G (p.Asn407Ser)	DHCR7	Pathogenic	criteria provided, single submitter
1457187	NM_001360.3(DHCR7):c.1228G>C (p.Gly410Arg)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457935	NM_001360.3(DHCR7):c.925G>A (p.Gly309Ser)	DHCR7	Pathogenic	criteria provided, single submitter
1457937	NM_001360.3(DHCR7):c.822C>A (p.Asn274Lys)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458037	NM_001360.3(DHCR7):c.575C>T (p.Ser192Phe)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166988	NM_001360.3(DHCR7):c.461C>G (p.Thr154Arg)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709241	NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188723	NM_001360.3(DHCR7):c.292C>T (p.Gln98Ter)	DHCR7	Pathogenic	criteria provided, multiple submitters, no conflicts
188923	NM_001360.3(DHCR7):c.461C>T (p.Thr154Met)	DHCR7	Pathogenic	criteria provided, multiple submitters, no conflicts
189069	NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189168	NM_001360.3(DHCR7):c.111G>A (p.Trp37Ter)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1949695	NM_001360.3(DHCR7):c.48_78del (p.Asp16fs)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198773	NM_001360.3(DHCR7):c.907G>A (p.Gly303Arg)	DHCR7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999612	NM_001360.3(DHCR7):c.1404C>G (p.Tyr468Ter)	DHCR7	Pathogenic	criteria provided, single submitter
2030429	NM_001360.3(DHCR7):c.474G>A (p.Trp158Ter)	DHCR7	Pathogenic	criteria provided, single submitter
2034234	NM_001360.3(DHCR7):c.546G>T (p.Trp182Cys)	DHCR7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DHCR7	Definitive	Autosomal recessive	Smith-Lemli-Opitz syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHCR7	Orphanet:818	Smith-Lemli-Opitz syndrome
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
CLCN1	Orphanet:614	Thomsen and Becker disease
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHCR7	HGNC:2860	ENSG00000172893	Q9UBM7	7-dehydrocholesterol reductase	gencc,clinvar
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	clinvar
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHCR7	7-dehydrocholesterol reductase	Oxidoreductase that catalyzes the last step of the cholesterol synthesis pathway, which transforms cholesta-5,7-dien-3beta-ol (7-dehydrocholesterol,7-DHC) into cholesterol by reducing the C7-C8 double bond of its sterol core.
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	6.0×	0.441
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHCR7	Enzyme (other)	yes	1.3.1.21	ERG24_DHCR-like, Sterol_reductase_CS
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
right adrenal gland cortex	1
right lobe of liver	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1
lower lobe of lung	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHCR7	257	ubiquitous	marker	adrenal tissue, right lobe of liver, right adrenal gland cortex
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHCR7	2,345
TSHR	1,672
LDLR	1,426
CLCN1	1,191

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDLR	P01130	36
TSHR	P16473	9
CLCN1	P35523	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHCR7	Q9UBM7	91.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cholesterol biosynthesis from zymosterol (modified Kandutsch-Russell pathway)	1	713.8×	0.018	DHCR7
Chylomicron clearance	1	571.0×	0.018	LDLR
Cholesterol biosynthesis via desmosterol (Bloch pathway)	1	285.5×	0.022	DHCR7
Hormone ligand-binding receptors	1	237.9×	0.022	TSHR
LDL clearance	1	135.9×	0.029	LDLR
Plasma lipoprotein clearance	1	119.0×	0.029	LDLR
Metabolism of fat-soluble vitamins	1	95.2×	0.031	LDLR
Visual phototransduction	1	64.9×	0.033	LDLR
Activation of gene expression by SREBF (SREBP)	1	64.9×	0.033	DHCR7
Retinoid metabolism and transport	1	62.1×	0.033	LDLR
Plasma lipoprotein assembly, remodeling, and clearance	1	57.1×	0.033	LDLR
Stimuli-sensing channels	1	34.0×	0.051	CLCN1
Metabolism of vitamins and cofactors	1	29.1×	0.055	LDLR
Cargo recognition for clathrin-mediated endocytosis	1	26.2×	0.056	LDLR
Sensory Perception	1	23.8×	0.058	LDLR
Clathrin-mediated endocytosis	1	21.3×	0.061	LDLR
G alpha (s) signalling events	1	18.3×	0.066	TSHR
Membrane Trafficking	1	9.3×	0.121	LDLR
Vesicle-mediated transport	1	8.7×	0.122	LDLR
Transport of small molecules	1	6.3×	0.157	LDLR
Metabolism	1	2.9×	0.302	LDLR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thyroid-stimulating hormone signaling pathway	1	4213.0×	0.006	TSHR
cellular response to thyrotropin-releasing hormone	1	4213.0×	0.006	TSHR
regulation of phosphatidylcholine catabolic process	1	2106.5×	0.006	LDLR
receptor-mediated endocytosis involved in cholesterol transport	1	2106.5×	0.006	LDLR
negative regulation of astrocyte activation	1	1404.3×	0.006	LDLR
cellular response to glycoprotein	1	1404.3×	0.006	TSHR
obsolete cholesterol biosynthetic process via desmosterol	1	1053.2×	0.006	DHCR7
plasma lipoprotein particle clearance	1	1053.2×	0.006	LDLR
negative regulation of receptor recycling	1	842.6×	0.006	LDLR
positive regulation of lysosomal protein catabolic process	1	842.6×	0.006	LDLR
cholesterol import	1	702.2×	0.006	LDLR
high-density lipoprotein particle clearance	1	601.9×	0.006	LDLR
lipoprotein catabolic process	1	601.9×	0.006	LDLR
obsolete cholesterol biosynthetic process via lathosterol	1	526.6×	0.006	DHCR7
regulation of protein metabolic process	1	526.6×	0.006	LDLR
negative regulation of protein metabolic process	1	526.6×	0.006	LDLR
amyloid-beta clearance by cellular catabolic process	1	526.6×	0.006	LDLR
negative regulation of microglial cell activation	1	526.6×	0.006	LDLR
negative regulation of low-density lipoprotein particle clearance	1	383.0×	0.007	LDLR
response to caloric restriction	1	383.0×	0.007	LDLR
positive regulation of ferroptosis	1	383.0×	0.007	DHCR7
neuronal action potential propagation	1	351.1×	0.007	CLCN1
intestinal cholesterol absorption	1	351.1×	0.007	LDLR
positive regulation of triglyceride biosynthetic process	1	324.1×	0.007	LDLR
negative regulation of amyloid fibril formation	1	324.1×	0.007	LDLR
regulation of cholesterol metabolic process	1	280.9×	0.008	LDLR
low-density lipoprotein particle clearance	1	247.8×	0.008	LDLR
amyloid-beta clearance	1	234.1×	0.009	LDLR
cellular response to low-density lipoprotein particle stimulus	1	221.7×	0.009	LDLR
cholesterol transport	1	183.2×	0.010	LDLR

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Simvastatin.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 1

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DHCR7	DOXORUBICIN
TSHR	LEVOSALBUTAMOL
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
DHCR7	2	4
LDLR	1	4
CLCN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DOXORUBICIN	4	DHCR7
TAMOXIFEN	4	DHCR7
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LDLR	55	Binding:54, Functional:1
DHCR7	43	Functional:23, Binding:20
TSHR	33	Functional:24, Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHCR7	1.3.1.21	7-dehydrocholesterol reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DOXORUBICIN	4	DHCR7
TAMOXIFEN	4	DHCR7
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	DHCR7, TSHR, LDLR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLCN1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE2	5
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00004347	PHASE2	UNKNOWN	Phase II Study of Dietary Cholesterol for Smith-Lemli-Opitz Syndrome
NCT00064792	PHASE2	COMPLETED	Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
NCT00114634	PHASE2	COMPLETED	Short-term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome
NCT00272844	PHASE1/PHASE2	COMPLETED	Treatment of the Cholesterol Defect in Smith-Lemli-Opitz Syndrome
NCT01110642	PHASE2	WITHDRAWN	Novel Treatment for Syndromic Ichthyoses
NCT03720990	PHASE1/PHASE2	COMPLETED	Smith-Lemli-Opitz Syndrome and Cholic Acid
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05047354	Not specified	RECRUITING	Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism
NCT00001721	Not specified	COMPLETED	Study of Smith-Lemli-Opitz Syndrome
NCT00017732	Not specified	COMPLETED	Estimation of the Carrier Frequency and Incidence of Smith-Lemli-Opitz Syndrome in African Americans
NCT00070850	Not specified	COMPLETED	Prenatal Screening For Smith-Lemli-Opitz Syndrome
NCT01356420	Not specified	TERMINATED	Sterol and Isoprenoid Disease Research Consortium: Smith-Lemli-Opitz Syndrome
NCT01434745	Not specified	TERMINATED	SLOS: The Effect of Simvastatin in Patients Receiving Cholesterol Supplementation
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SIMVASTATIN	4	2
CHOLIC ACID	4	1
LOVASTATIN	4	1
LACTOSE, ANHYDROUS	3	1
CHOLESTEROL	2	3
CHEMBL1867358	0	3
CHEMBL3184306	0	3