Classic homocystinuria

Summary

Classic homocystinuria (MONDO:0009352) is a disease caused by CBS (GenCC Definitive), with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include acetaminophen.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: CBS (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 446
• Phenotypes (HPO): 62
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

9 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.65	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.5	Ireland	Validated
Prevalence at birth	1-9 / 1 000 000	0.77	Germany	Validated
Prevalence at birth	1-5 / 10 000	15.6	Norway	Validated
Prevalence at birth	1-9 / 100 000	5	Denmark	Validated
Prevalence at birth	1-9 / 100 000	1.7	Australia	Validated
Prevalence at birth	1-5 / 10 000	55.5	Qatar	Validated
Prevalence at birth	1-9 / 1 000 000	0.11	Japan	Validated
Prevalence at birth	1-9 / 1 000 000	0.3	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000678	Dental crowding	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0001083	Ectopia lentis	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001519	Disproportionate tall stature	Very frequent (80-99%)
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0004337	Abnormality of amino acid metabolism	Very frequent (80-99%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002204	Pulmonary embolism	Frequent (30-79%)
HP:0002209	Sparse scalp hair	Frequent (30-79%)
HP:0002637	Cerebral ischemia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0004420	Arterial thrombosis	Frequent (30-79%)
HP:0004936	Venous thrombosis	Frequent (30-79%)
HP:0100026	Arteriovenous malformation	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001010	Hypopigmentation of the skin	Occasional (5-29%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001132	Lens subluxation	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0001933	Subcutaneous hemorrhage	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	classic homocystinuria
Mondo ID	MONDO:0009352
OMIM	236200
Orphanet	394
SNOMED CT	24308003
UMLS	C0751202
MedGen	199606
GARD	0006667
MedDRA	10071093
NORD	1249
Is cancer (heuristic)	no

Also known as: CBS deficiency · classic homocystinuria · cystathionine beta-synthase deficiency · homocystinuria due to CBS deficiency · Homocystinuria due to Cystathionine Beta-Synthase Deficiency · homocystinuria due to cystathionine beta-synthase deficiency · homocystinuria, B6-responsive and nonresponsive types · thrombosis, hyperhomocysteinemic

Data availability: 446 ClinVar variants · 6 GenCC gene-disease records · 27 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › classic homocystinuria

Related subtypes (9): lens subluxation, posterior dislocation of lens, cataract, blepharoptosis-myopia-ectopia lentis syndrome, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, congenital primary aphakia, ectopia lentis-chorioretinal dystrophy-myopia syndrome, isolated ectopia lentis, encephalopathy due to sulfite oxidase deficiency

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

446 retrieved; paginated sample, class counts are floors:

142 uncertain significance, 85 likely pathogenic, 61 pathogenic/likely pathogenic, 59 conflicting classifications of pathogenicity, 45 pathogenic, 24 likely benign, 19 benign/likely benign, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1052953	NM_000071.3(CBS):c.1007G>C (p.Arg336Pro)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066972	NM_000071.3(CBS):c.869C>T (p.Pro290Leu)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070052	NM_000071.3(CBS):c.262C>T (p.Pro88Ser)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073191	NM_000071.3(CBS):c.1397C>A (p.Ser466Ter)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1075453	NM_000071.3(CBS):c.98del (p.Pro33fs)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076336	NC_000021.8:g.(?44478245)(44485815_?)del	CBS	Pathogenic	criteria provided, single submitter
117	NM_000071.3(CBS):c.919G>A (p.Gly307Ser)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
118	NM_000071.3(CBS):c.434C>T (p.Pro145Leu)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
119	NM_000071.3(CBS):c.341C>T (p.Ala114Val)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120	NM_000071.3(CBS):c.833T>C (p.Ile278Thr)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
122	NM_000071.3(CBS):c.430G>A (p.Glu144Lys)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
125	NM_000071.3(CBS):c.797G>A (p.Arg266Lys)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126	NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128	NM_000071.3(CBS):c.1224-2A>C	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
131	NM_000071.3(CBS):c.1058C>T (p.Thr353Met)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
132	NM_000071.3(CBS):c.572C>T (p.Thr191Met)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1326932	NM_000071.3(CBS):c.667-1G>C	CBS	Pathogenic	no assertion criteria provided
1452450	NM_000071.3(CBS):c.481del (p.Arg161fs)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1481680	NM_000071.3(CBS):c.473C>T (p.Ala158Val)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1501269	NM_000071.3(CBS):c.210-1G>C	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188784	NM_000071.3(CBS):c.1566del (p.Lys523fs)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188787	NM_000071.3(CBS):c.346G>A (p.Gly116Arg)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188801	NM_000071.3(CBS):c.1039G>A (p.Gly347Ser)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188825	NM_000071.3(CBS):c.1136G>A (p.Arg379Gln)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188829	NM_000071.3(CBS):c.689del (p.Leu230fs)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
188911	NM_000071.3(CBS):c.667-14_667-7del	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188927	NM_000071.3(CBS):c.770C>T (p.Thr257Met)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188948	NM_000071.3(CBS):c.362G>A (p.Arg121His)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189081	NM_000071.3(CBS):c.1358+1G>A	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
189185	NM_000071.3(CBS):c.302T>C (p.Leu101Pro)	CBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
CBS	Definitive	Autosomal recessive	classic homocystinuria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBS	Orphanet:394	Homocystinuria due to cystathionine beta-synthase deficiency
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CBS	HGNC:1550	ENSG00000160200	P35520	Cystathionine beta-synthase	gencc,clinvar
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	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.
PKHD1	Fibrocystin	Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney.

Protein-family classification

Druggable: 2 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

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
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
liver	1
right lobe of liver	1
kidney epithelium	1
metanephros cortex	1
renal medulla	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
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PKHD1	1,211
CBS	346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBS	P35520	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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 2 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	8426.0×	0.002	CBS
regulation of cholangiocyte proliferation	1	8426.0×	0.002	PKHD1
obsolete regulation of nitric oxide mediated signal transduction	1	4213.0×	0.002	CBS
obsolete L-cysteine biosynthetic process via L-cystathionine	1	4213.0×	0.002	CBS
L-cysteine biosynthetic process	1	2808.7×	0.002	CBS
cerebellum morphogenesis	1	2808.7×	0.002	CBS
L-homocysteine catabolic process	1	2808.7×	0.002	CBS
hydrogen sulfide biosynthetic process	1	2808.7×	0.002	CBS
L-serine catabolic process	1	2106.5×	0.002	CBS
transsulfuration	1	2106.5×	0.002	CBS
L-cysteine catabolic process	1	2106.5×	0.002	CBS
DNA protection	1	1404.3×	0.002	CBS
regulation of establishment of planar polarity	1	1404.3×	0.002	PKHD1
response to folic acid	1	1203.7×	0.002	CBS
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.002	CBS
negative regulation of apoptotic process	2	34.8×	0.002	CBS, PKHD1
homocysteine metabolic process	1	936.2×	0.003	CBS
L-serine metabolic process	1	842.6×	0.003	CBS
homeostatic process	1	842.6×	0.003	PKHD1
establishment of centrosome localization	1	842.6×	0.003	PKHD1
regulation of cell-matrix adhesion	1	648.1×	0.003	PKHD1
regulation of cell-cell adhesion	1	601.9×	0.003	PKHD1
negative regulation of epithelial cell apoptotic process	1	601.9×	0.003	PKHD1
superoxide metabolic process	1	495.6×	0.004	CBS
epithelial cell morphogenesis	1	468.1×	0.004	PKHD1
regulation of TOR signaling	1	468.1×	0.004	PKHD1
maternal process involved in female pregnancy	1	468.1×	0.004	CBS
regulation of JNK cascade	1	443.5×	0.004	CBS
regulation of centrosome duplication	1	366.4×	0.004	PKHD1
branching morphogenesis of an epithelial tube	1	366.4×	0.004	PKHD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PKHD1	0	0

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: 2; 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	1	PKHD1
E	Difficult family or no structure, no drug	0

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)
PKHD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04015557	PHASE1/PHASE2	SUSPENDED	Effect of Acetaminophen and N-Acetylcysteine on Liver Metabolism on Homocystinuria
NCT05154890	PHASE1/PHASE2	TERMINATED	A Multiple Ascending Dose Study of ACN00177 (Pegtarviliase) in Subjects With CBS Deficiency
NCT02998710	Not specified	RECRUITING	Natural History Study of Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency (ACAPPELLA)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACETAMINOPHEN	4	1