Hyperhomocysteinemia

Summary

Hyperhomocysteinemia (MONDO:0004743) is a disease with 1 cohort gene and 28 clinical trials. Top therapeutic interventions include folic acid, enalapril, and pyridoxine.

At a glance

• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperhomocysteinemia
Mondo ID	MONDO:0004743
MeSH	D020138
OMIM	603174
DOID	DOID:9279
NCIT	C84770
SNOMED CT	419503008
UMLS	C0598608
MedGen	108623
GARD	0008230
Is cancer (heuristic)	no

Also known as: homocysteinemia · hyperhomocysteinemia

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › homocystinuria › hyperhomocysteinemia

Related subtypes (4): classic homocystinuria, homocystinuria due to methylene tetrahydrofolate reductase deficiency, methylmalonic aciduria and homocystinuria, homocystinuria without methylmalonic aciduria

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
188927	NM_000071.3(CBS):c.770C>T (p.Thr257Met)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBS	Orphanet:394	Homocystinuria due to cystathionine beta-synthase deficiency

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
CBS	HGNC:1550	ENSG00000160200	P35520	Cystathionine beta-synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBS	Cystathionine beta-synthase	Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine.

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)
CBS	Enzyme (other)	yes	4.2.1.22	CBS_dom, P-phosphate_BS, TrpB-like_PALP

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
body of pancreas	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBS	134	tissue_specific	marker	right lobe of liver, body of pancreas, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CBS	346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBS	P35520	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Cysteine formation from homocysteine	1	5710.0×	0.001	CBS
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	1427.5×	0.002	CBS
Sulfur amino acid metabolism	1	571.0×	0.004	CBS
Selenoamino acid metabolism	1	196.9×	0.008	CBS
Metabolism of amino acids and derivatives	1	67.6×	0.018	CBS
Metabolism	1	11.6×	0.086	CBS

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 L-cysteine biosynthetic process from L-serine	1	16852.0×	5e-04	CBS
obsolete regulation of nitric oxide mediated signal transduction	1	8426.0×	5e-04	CBS
obsolete L-cysteine biosynthetic process via L-cystathionine	1	8426.0×	5e-04	CBS
L-cysteine biosynthetic process	1	5617.3×	5e-04	CBS
cerebellum morphogenesis	1	5617.3×	5e-04	CBS
L-homocysteine catabolic process	1	5617.3×	5e-04	CBS
hydrogen sulfide biosynthetic process	1	5617.3×	5e-04	CBS
L-serine catabolic process	1	4213.0×	5e-04	CBS
transsulfuration	1	4213.0×	5e-04	CBS
L-cysteine catabolic process	1	4213.0×	5e-04	CBS
DNA protection	1	2808.7×	7e-04	CBS
response to folic acid	1	2407.4×	7e-04	CBS
cartilage development involved in endochondral bone morphogenesis	1	2407.4×	7e-04	CBS
homocysteine metabolic process	1	1872.4×	9e-04	CBS
L-serine metabolic process	1	1685.2×	9e-04	CBS
superoxide metabolic process	1	991.3×	0.001	CBS
maternal process involved in female pregnancy	1	936.2×	0.001	CBS
regulation of JNK cascade	1	887.0×	0.001	CBS
blood vessel diameter maintenance	1	624.1×	0.002	CBS
endochondral ossification	1	543.6×	0.002	CBS
blood vessel remodeling	1	383.0×	0.003	CBS
cellular response to hypoxia	1	121.2×	0.009	CBS
negative regulation of apoptotic process	1	34.8×	0.029	CBS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CBS	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HYPERICIN	3	CBS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CBS	22	Binding:22

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CBS	4.2.1.22	cystathionine beta-synthase

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)
HYPERICIN	3	CBS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	CBS
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: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	19
PHASE4	4
PHASE3	2
PHASE1	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00317005	PHASE4	COMPLETED	Uremic Hyperhomocysteinemia -A Folate Trial for Possible Prevention of Cardiovascular Events
NCT01766310	PHASE4	COMPLETED	Effect of Folic Acid Supplementation on Plasma Homocysteine Level in Obese Children
NCT01871740	PHASE4	WITHDRAWN	CSPPT- Chronic Kidney Diseases Study
NCT02817503	PHASE4	UNKNOWN	Feasibility Study of the Intensive Systolic Blood Pressure Control
NCT00755664	PHASE3	COMPLETED	Effects of Low-dose Complex B-vitamins on Homocysteine and Framingham Risk Score Among Chinese Elderly
NCT01371357	PHASE3	COMPLETED	The Effects of 8-week Choline, Betaine, and Folic Acid Supplementation on Plasma Homocysteine Concentration During Guanidinoacetic Acid Loading in Young Healthy Volunteers
NCT03431597	PHASE2	COMPLETED	Effectiveness of a Micronutrient Supplement to Lower Plasma Homocysteine MDEG2 Pilot Supplementation Trial
NCT00473200	PHASE1	COMPLETED	Effect of S-adenosylmethionine (SAMe) on Blood Levels of Homocysteine
NCT00877227	PHASE1	COMPLETED	Does B Vitamin Supplementation Decrease Homocysteine Concentrations in Newborns
NCT06264570	Not specified	RECRUITING	Evaluation of a Genetically Determined Personalized Approach in Prescribing Biologically Active Substances in Patients With Elevated Blood Homocysteine Levels.
NCT07480265	Not specified	RECRUITING	Homocysteine and Early Diastolic Dysfunction in Newly Diagnosed Hypertension
NCT00004495	Not specified	COMPLETED	Randomized Study of Folic Acid Therapy for Hyperhomocysteinemia in Patients With End Stage Renal Disease Receiving Hemodialysis
NCT00005338	Not specified	COMPLETED	Homocysteine and Progression of Atherosclerosis
NCT00005482	Not specified	COMPLETED	Homocyst(e)Ine, Vitamin Status, and CVD Risk
NCT00005483	Not specified	COMPLETED	Plasma Homocysteine Distribution in the United States
NCT00626223	Not specified	COMPLETED	5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients
NCT00737126	Not specified	COMPLETED	The Effect of Folic Acid Administration in the Progression of Microalbuminuria
NCT01391416	Not specified	COMPLETED	Prevalence Of Hyperhomocysteinemia In Thai Chronic Kidney Disease (CKD) Patients
NCT02392767	Not specified	COMPLETED	Effect of L-Arginine and Pycnogenol on Light to Moderate Hypertension and Endothelial Function
NCT02540642	Not specified	COMPLETED	Effect of Vitamin B12 Supplementation on Glycaemic Control in Uncontrolled Hyperhomocysteinemic Type 2 Diabetic Patients
NCT02860338	Not specified	COMPLETED	COMPARATIVE EFFECTIVENESS OF MCI and DEMENTIA TREATMENTS IN A COMMUNITY-BASED DEMENTIA PRACTICE
NCT02961972	Not specified	COMPLETED	Effects of Oral Supplementation With Creatine on Systemic Microvascular Endothelial Function in Vegetarian Individuals
NCT03376490	Not specified	COMPLETED	Study of the Association of Muscle Strength, Balance and Other Factors With Vitamin Levels Among Elderly Diabetics
NCT03631238	Not specified	COMPLETED	The Dual Impact of Homocysteine and Cholesterol on Cognitive Functions
NCT03720249	Not specified	UNKNOWN	Effects of Supplementation of Compound Nutrients on Plasma Homocysteine in Chinese Adults With Hyperhomocysteinemia
NCT05080153	Not specified	COMPLETED	Effect of Vitamin Supplementation in Glaucoma Patients
NCT06163443	Not specified	COMPLETED	Evaluating the Impact of B Vitamin Supplementation (Soloways™) on Homocysteine and LDL-C Levels in Patients With MTHFR, MTR, and MTRR Polymorphisms.
NCT06959446	Not specified	COMPLETED	Perioperative Homocysteine and Postoperative Complications/All-Cause Mortality in Elderly Non-Cardiac Surgery Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FOLIC ACID	4	6
ENALAPRIL	4	3
PYRIDOXINE	4	3
CYANOCOBALAMIN	4	1
LEVOMEFOLIC ACID	4	1
ADEMETIONINE	3	1
METHYLCOBALAMIN	2	1
CHEMBL1235831	0	1
HOMOCYSTEINE	0	1
L-HOMOCYSTEINE	0	1