Desmosterolosis

Summary

Desmosterolosis (MONDO:0011217) is a disease caused by DHCR24 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DHCR24 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 108
• Phenotypes (HPO): 57
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000176	Submucous cleft hard palate	Very frequent (80-99%)
HP:0000193	Bifid uvula	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001331	Absent septum pellucidum	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0003552	Muscle stiffness	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0009748	Large earlobe	Frequent (30-79%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000363	Abnormality of earlobe	Frequent (30-79%)
HP:0000366	Abnormality of the nose	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0000104	Renal agenesis	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0001339	Lissencephaly	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001840	Metatarsus adductus	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002269	Abnormality of neuronal migration	Occasional (5-29%)
HP:0002536	Abnormal cortical gyration	Occasional (5-29%)
HP:0002566	Intestinal malrotation	Occasional (5-29%)
HP:0002983	Micromelia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	desmosterolosis
Mondo ID	MONDO:0011217
MeSH	C566555
OMIM	602398
Orphanet	35107
DOID	DOID:0070654
ICD-11	2108931494
SNOMED CT	709490002
UMLS	C1865596
MedGen	400801
GARD	0010283
Is cancer (heuristic)	no

Also known as: desmosterolosis

Data availability: 108 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › neonatal osteosclerotic dysplasia › desmosterolosis

Related subtypes (4): Caffey disease, chondrodysplasia Blomstrand type, lethal osteosclerotic bone dysplasia, dysplastic cortical hyperostosis

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

108 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 18 benign, 16 likely benign, 10 conflicting classifications of pathogenicity, 4 likely pathogenic, 4 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4368	NM_014762.3(DHCR24):c.[881A>C,918G>C]		Pathogenic	no assertion criteria provided
30576	NM_014762.4(DHCR24):c.307C>T (p.Arg103Cys)	DHCR24	Pathogenic	no assertion criteria provided
1027890	NM_014762.4(DHCR24):c.958G>T (p.Glu320Ter)	DHCR24	Likely pathogenic	criteria provided, single submitter
30577	NM_014762.4(DHCR24):c.281G>A (p.Arg94His)	DHCR24	Likely pathogenic	criteria provided, single submitter
4367	NM_014762.4(DHCR24):c.1412A>C (p.Tyr471Ser)	DHCR24	Likely pathogenic	criteria provided, single submitter
4369	NM_014762.4(DHCR24):c.571G>A (p.Glu191Lys)	DHCR24	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1187094	NM_014762.4(DHCR24):c.1460G>A (p.Gly487Asp)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297626	NM_014762.4(DHCR24):c.*1489G>A	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297658	NM_014762.4(DHCR24):c.726C>A (p.Phe242Leu)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297661	NM_014762.4(DHCR24):c.615C>T (p.Ser205=)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30578	NM_014762.4(DHCR24):c.1438G>A (p.Glu480Lys)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3384675	NM_014762.4(DHCR24):c.1055G>A (p.Arg352His)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807404	NM_014762.4(DHCR24):c.1532G>A (p.Cys511Tyr)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807405	NM_014762.4(DHCR24):c.1504G>A (p.Ala502Thr)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874282	NM_014762.4(DHCR24):c.616G>A (p.Glu206Lys)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876127	NM_014762.4(DHCR24):c.1329G>A (p.Pro443=)	DHCR24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184322	NM_014762.4(DHCR24):c.286G>C (p.Gly96Arg)	DHCR24	Uncertain significance	criteria provided, single submitter
1310018	NM_014762.4(DHCR24):c.463G>A (p.Val155Met)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
1439868	NM_014762.4(DHCR24):c.1331G>A (p.Arg444His)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
1499036	NM_014762.4(DHCR24):c.1024A>G (p.Ile342Val)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
2789015	NM_014762.4(DHCR24):c.313G>A (p.Gly105Arg)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
281353	NM_014762.4(DHCR24):c.811C>A (p.Leu271Ile)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
284658	NM_014762.4(DHCR24):c.731C>T (p.Pro244Leu)	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
297614	NM_014762.4(DHCR24):c.*2514A>G	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts
297615	NM_014762.4(DHCR24):c.*2503C>T	DHCR24	Uncertain significance	criteria provided, single submitter
297618	NM_014762.4(DHCR24):c.*2245A>T	DHCR24	Uncertain significance	criteria provided, single submitter
297619	NM_014762.4(DHCR24):c.*2119C>T	DHCR24	Uncertain significance	criteria provided, single submitter
297620	NM_014762.4(DHCR24):c.*2080C>T	DHCR24	Uncertain significance	criteria provided, single submitter
297622	NM_014762.4(DHCR24):c.*1881G>A	DHCR24	Uncertain significance	criteria provided, single submitter
297628	NM_014762.4(DHCR24):c.*1424C>T	DHCR24	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
DHCR24	Definitive	Autosomal recessive	desmosterolosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHCR24	Orphanet:35107	Desmosterolosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHCR24	HGNC:2859	ENSG00000116133	Q15392	Delta(24)-sterol reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHCR24	Delta(24)-sterol reductase	Catalyzes the reduction of the delta-24 double bond of sterol intermediates during cholesterol biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHCR24	Enzyme (other)	yes	1.3.1.72	Oxid_FAD_bind_N, FAD-bd_PCMH, FAD-bd_PCMH_sub2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHCR24	281	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHCR24	3,150

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHCR24	Q15392	92.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 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	2855.0×	9e-04	DHCR24
Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)	1	1268.9×	9e-04	DHCR24
Cholesterol biosynthesis via desmosterol (Bloch pathway)	1	1142.0×	9e-04	DHCR24

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete cholesterol biosynthetic process via desmosterol	1	4213.0×	0.002	DHCR24
obsolete cholesterol biosynthetic process via lathosterol	1	2106.5×	0.002	DHCR24
tissue development	1	1872.4×	0.002	DHCR24
plasminogen activation	1	1296.3×	0.002	DHCR24
amyloid precursor protein catabolic process	1	1203.7×	0.002	DHCR24
male genitalia development	1	887.0×	0.003	DHCR24
membrane organization	1	510.7×	0.003	DHCR24
skin development	1	443.5×	0.003	DHCR24
response to hormone	1	432.1×	0.003	DHCR24
cholesterol biosynthetic process	1	421.3×	0.003	DHCR24
steroid metabolic process	1	337.0×	0.004	DHCR24
Ras protein signal transduction	1	205.5×	0.006	DHCR24
intracellular protein localization	1	104.7×	0.010	DHCR24
negative regulation of cell population proliferation	1	42.1×	0.024	DHCR24

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
DHCR24	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DHCR24	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GILTERITINIB	4	DHCR24

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DHCR24	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHCR24	1.3.1.72	DELTA24-sterol reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
GILTERITINIB	4	DHCR24

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DHCR24
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05047354	Not specified	RECRUITING	Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism