Rickets

Summary

Rickets (MONDO:0005520) is a disease with 3 cohort genes and 67 clinical trials. Top therapeutic interventions include cholecalciferol, calcium, and calcium carbonate.

At a glance

• Cohort genes: 3
• ClinVar variants: 3
• Clinical trials: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	rickets
Mondo ID	MONDO:0005520
EFO	EFO:0005583
MeSH	D012279
DOID	DOID:10609
NCIT	C26878
SNOMED CT	41345002
UMLS	C0035579
MedGen	48470
GARD	0005700
Is cancer (heuristic)	no

Also known as: hypovitaminosis D · nutritional rickets · rachitis · rickets · rickets (disease) · vitamin D deficiency disease · vitamin D hydroxylation-deficient rickets · vitamin-D deficiency rickets

Data availability: 3 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › rickets

Related subtypes (5): bone resorption disease, fibrous dysplasia, osteomalacia, hyperostosis, osteosclerosis

Subtypes (4): renal osteodystrophy, hypocalcemic rickets, vitamin D-dependent rickets, hypophosphatemic rickets

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
915348	NM_000376.3(VDR):c.821G>A (p.Arg274His)	VDR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694733	NM_001128831.4(CA1):c.368_369del (p.His123fs)	CA1	Uncertain significance	criteria provided, single submitter
830363	NM_000183.3(HADHB):c.110-2324G>C	HADHB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VDR	Orphanet:93160	Hypocalcemic vitamin D-resistant rickets
HADHB	Orphanet:746	Mitochondrial trifunctional protein deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VDR	HGNC:12679	ENSG00000111424	P11473	Vitamin D3 receptor	clinvar
CA1	HGNC:1368	ENSG00000133742	P00915	Carbonic anhydrase 1	clinvar
HADHB	HGNC:4803	ENSG00000138029	P55084	Trifunctional enzyme subunit beta, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VDR	Vitamin D3 receptor	Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells.
CA1	Carbonic anhydrase 1	Catalyzes the reversible hydration of carbon dioxide.
HADHB	Trifunctional enzyme subunit beta, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Nuclear receptor	1	128.6×	0.023
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VDR	Nuclear receptor	yes		VitD_rcpt, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
CA1	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
HADHB	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hair follicle	1
jejunal mucosa	1
tibia	1
colonic mucosa	1
mucosa of transverse colon	1
trabecular bone tissue	1
deltoid	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VDR	224	ubiquitous	marker	tibia, hair follicle, jejunal mucosa
CA1	177	tissue_specific	marker	mucosa of transverse colon, trabecular bone tissue, colonic mucosa
HADHB	295	ubiquitous	marker	heart right ventricle, left ventricle myocardium, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHB	4,047
CA1	1,800
VDR	354

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CA1	P00915	56
VDR	P11473	52
HADHB	P55084	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Beta oxidation of myristoyl-CoA to lauroyl-CoA	1	1268.9×	0.005	HADHB
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	1	1268.9×	0.005	HADHB
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	761.3×	0.005	HADHB
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	761.3×	0.005	HADHB
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	761.3×	0.005	HADHB
Acyl chain remodeling of CL	1	634.4×	0.005	HADHB
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	634.4×	0.005	HADHB
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	634.4×	0.005	HADHB
Erythrocytes take up oxygen and release carbon dioxide	1	423.0×	0.005	CA1
O2/CO2 exchange in erythrocytes	1	423.0×	0.005	CA1
Reversible hydration of carbon dioxide	1	317.2×	0.006	CA1
Erythrocytes take up carbon dioxide and release oxygen	1	292.8×	0.006	CA1
Vitamin D (calciferol) metabolism	1	292.8×	0.006	VDR
Interleukin-12 family signaling	1	158.6×	0.010	CA1
Interleukin-12 signaling	1	135.9×	0.011	CA1
SUMOylation of intracellular receptors	1	112.0×	0.013	VDR
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	100.2×	0.013	CA1
Nuclear Receptor transcription pathway	1	66.8×	0.019	VDR
Signaling by Interleukins	1	21.4×	0.056	CA1
Cytokine Signaling in Immune system	1	13.6×	0.083	CA1
Transport of small molecules	1	8.4×	0.126	CA1
Immune System	1	4.3×	0.224	CA1
Metabolism	1	3.9×	0.237	CA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear receptor-mediated bile acid signaling pathway	1	2808.7×	0.004	VDR
response to bile acid	1	2808.7×	0.004	VDR
apoptotic process involved in mammary gland involution	1	1872.4×	0.004	VDR
positive regulation of apoptotic process involved in mammary gland involution	1	1404.3×	0.004	VDR
mammary gland branching involved in pregnancy	1	1404.3×	0.004	VDR
vitamin D receptor signaling pathway	1	936.2×	0.005	VDR
positive regulation of vitamin D receptor signaling pathway	1	936.2×	0.005	VDR
response to fructose	1	802.5×	0.005	CA1
phosphate ion transmembrane transport	1	401.2×	0.008	VDR
intestinal absorption	1	401.2×	0.008	VDR
intracellular receptor signaling pathway	1	330.4×	0.009	VDR
positive regulation of keratinocyte differentiation	1	267.5×	0.010	VDR
negative regulation of keratinocyte proliferation	1	234.1×	0.010	VDR
decidualization	1	224.7×	0.010	VDR
retinoic acid receptor signaling pathway	1	216.1×	0.010	VDR
lactation	1	140.4×	0.014	VDR
positive regulation of bone mineralization	1	130.6×	0.014	VDR
fatty acid beta-oxidation	1	124.8×	0.014	HADHB
mRNA transcription by RNA polymerase II	1	110.1×	0.015	VDR
calcium ion transport	1	60.4×	0.026	VDR
cell morphogenesis	1	52.5×	0.028	VDR
intracellular calcium ion homeostasis	1	48.4×	0.029	VDR
skeletal system development	1	41.9×	0.032	VDR
cellular response to lipopolysaccharide	1	32.7×	0.039	HADHB
gene expression	1	26.6×	0.046	HADHB
negative regulation of cell population proliferation	1	14.0×	0.083	VDR
positive regulation of gene expression	1	12.9×	0.087	VDR
negative regulation of DNA-templated transcription	1	10.5×	0.102	VDR
cell differentiation	1	9.7×	0.106	VDR
negative regulation of transcription by RNA polymerase II	1	5.9×	0.165	VDR

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 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
VDR	CHOLECALCIFEROL
CA1	METHAZOLAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CA1	70	4
VDR	10	4
HADHB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHOLECALCIFEROL	4	VDR
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
METHAZOLAMIDE	4	CA1
ACETAZOLAMIDE	4	CA1
ZONISAMIDE	4	CA1
TRICHLORMETHIAZIDE	4	CA1
CHLORTHALIDONE	4	CA1
ACETAMINOPHEN	4	CA1
NITROUS ACID	4	CA1
CELECOXIB	4	CA1
SULFUR	4	CA1
LEVETIRACETAM	4	CA1
SODIUM ACETATE	4	CA1
PHENOL	4	CA1
DICHLORPHENAMIDE	4	CA1
ETHOXZOLAMIDE	4	CA1
SULFANILAMIDE	4	CA1
VERALIPRIDE	4	CA1
DORZOLAMIDE	4	CA1
BRINZOLAMIDE	4	CA1
TOPIRAMATE	4	CA1
NILOTINIB	4	CA1
SULPIRIDE	4	CA1
BORTEZOMIB	4	CA1
SULTHIAME	4	CA1
FUROSEMIDE	4	CA1
INDAPAMIDE	4	CA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CA1	886	Binding:852, ADMET:32, Functional:2
VDR	561	Binding:459, Functional:99, ADMET:3
HADHB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CA1	4.2.1.1	carbonic anhydrase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
VDR	561
CA1	886

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
METHAZOLAMIDE	4	CA1
ACETAZOLAMIDE	4	CA1
ZONISAMIDE	4	CA1
TRICHLORMETHIAZIDE	4	CA1
CHLORTHALIDONE	4	CA1
ACETAMINOPHEN	4	CA1
NITROUS ACID	4	CA1
CELECOXIB	4	CA1
SULFUR	4	CA1
LEVETIRACETAM	4	CA1
SODIUM ACETATE	4	CA1
PHENOL	4	CA1
DICHLORPHENAMIDE	4	CA1
ETHOXZOLAMIDE	4	CA1
SULFANILAMIDE	4	CA1
VERALIPRIDE	4	CA1
DORZOLAMIDE	4	CA1
BRINZOLAMIDE	4	CA1
TOPIRAMATE	4	CA1
NILOTINIB	4	CA1
SULPIRIDE	4	CA1
BORTEZOMIB	4	CA1
SULTHIAME	4	CA1
FUROSEMIDE	4	CA1
INDAPAMIDE	4	CA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	VDR, CA1
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	HADHB

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)
HADHB	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 67.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	46
PHASE3	10
PHASE4	4
PHASE2	4
PHASE2/PHASE3	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00949832	PHASE4	COMPLETED	Vitamin D and Genetics in Nutritional Rickets
NCT01067898	PHASE4	COMPLETED	A Study on Oral Vitamin D Megadoses
NCT01578434	PHASE4	COMPLETED	Role of Calcium And Vitamin D In Nutritional Rickets And It’s Management
NCT03403933	PHASE4	COMPLETED	Vitamin D Supplementation on in Major Orthopedic Surgery
NCT00960232	PHASE3	COMPLETED	Vitamin D, Blood Pressure, Lipids, Infection and Depression
NCT01012414	PHASE3	TERMINATED	Effect of Vitamin D Supplement on Inflammation Markers in High-Risk Cardiovascular Patients With Chronic Kidney Disease
NCT01240265	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation in Breastfeeding Women
NCT01315366	PHASE3	COMPLETED	Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism
NCT01689779	PHASE3	COMPLETED	High Dose Preoperative Cholecalciferol Supplementation and Perioperative Vitamin D Status
NCT01896544	PHASE3	COMPLETED	Cholecalciferol Supplementation for Sepsis in the ICU
NCT02328404	PHASE3	COMPLETED	The Effect of Vitamin D Supplementation Among Overweight Jordanian Women With Polycystic Ovary Syndrome (PCOS)
NCT02434380	PHASE3	COMPLETED	Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes
NCT03272126	PHASE3	COMPLETED	Importance of Dosing Regimen for the Effect of Vitamin D Supplementation
NCT05306704	PHASE3	COMPLETED	High-Dose Vitamin D3 Supplementation in the Treatment of Human Immune Deficiency Virus Patients Trial
NCT05310760	PHASE2/PHASE3	COMPLETED	Effectiveness of Vitamin C Supplementation in Treatment of Rickets
NCT05425914	PHASE3	COMPLETED	Impact of Vitamin D3 Supplementation in Non-Sjogren Dry Eye Patients With Low Serum Vitamin D Level
NCT00001151	PHASE2	TERMINATED	Studies With 1,25-Dihydroxycholecalciferol
NCT00992797	PHASE2	UNKNOWN	Diabetes Intervention Trial With Vitamin D in Subjects of Nordic and Sub-Indian Ethnicity
NCT01656070	PHASE2	COMPLETED	Vitamin D Supplementation in HIV-infected Youth
NCT02452762	PHASE2	COMPLETED	Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial
NCT03771105	EARLY_PHASE1	RECRUITING	The Impact of Phosphate Metabolism on Healthy Aging
NCT05214040	Not specified	NOT_YET_RECRUITING	Vitamin D Insufficiency inVestigation Among hospitaLizeD Inpatients
NCT06138249	Not specified	RECRUITING	Cholecalciferol and Calcifediol Are Both Useful to Improve Vitamin D Serum Levels
NCT06481111	Not specified	RECRUITING	Prospective Monocentric Registry of Patients Undergoing Vitamin D Treatment at San Raffaele Hospital
NCT07096414	Not specified	RECRUITING	Effect of Vitamin D3 Supplementation on Brain Waves in Male Epileptic Patients With Hypovitaminosis D
NCT07143552	Not specified	RECRUITING	Bone Outcomes, Obesity, Sunlight, and Trauma in Children
NCT07199829	Not specified	RECRUITING	Evaluating Response to Vitamin D3 and K2 Supplementation in Healthcare Personnel
NCT07579078	Not specified	ENROLLING_BY_INVITATION	Effect of Vitamin D Supplementation on Brain Waves in Female Major Depressive Disorder Patients With Hypovitaminosis D
NCT00001242	Not specified	COMPLETED	Studies of States With Resistance to Vitamin D and Parathyroid Hormone
NCT00204906	Not specified	COMPLETED	Correction of Vitamin D Inadequacy in Nursing Home Residents
NCT00423358	Not specified	COMPLETED	Treatment of Hypovitaminosis D in Rheumatoid Arthritis
NCT00502866	Not specified	COMPLETED	Study to Assess the Use of a Simple Lab Test to Screen for Rickets in Children
NCT00662844	Not specified	COMPLETED	Vitamin D Supplementation in Younger Women
NCT00695474	Not specified	COMPLETED	Vitamin D and Type 2 Diabetes - a Cross Sectional Study
NCT00887666	Not specified	COMPLETED	Pilot Study: Hypovitaminosis D, Hyperparathyroidism and Hypomagnesemia in Patients With Congestive Heart Failure
NCT00944606	Not specified	WITHDRAWN	Vitamin D Versus Placebo in the Treatment of Vague Musculoskeletal Pain in Children
NCT01023490	Not specified	COMPLETED	Vitamin D Treatment to Patients Suffering From Chronic Pain and Vitamin D Hypovitaminosis
NCT01057186	Not specified	UNKNOWN	Hypophosphatemic Rickets in Norway
NCT01240213	Not specified	COMPLETED	Vitamin D, Diet and Activity Study
NCT01524874	Not specified	COMPLETED	Comparative Effectiveness of Vitamin D and Repletion Strategies

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHOLECALCIFEROL	4	26
CALCIUM	4	2
CALCIUM CARBONATE	4	2
ERGOCALCIFEROL	4	2
CALCIFEDIOL	4	1
OLIVE OIL	4	1
PARICALCITOL	4	1
RISEDRONIC ACID	4	1
SEVELAMER	4	1
25-HYDROXYERGOCALCIFEROL-	3	1
ORANGE JUICE	1	1
CHEMBL5072826	0	2
CHEMBL50241	0	1