Orthostatic hypotension 1

Summary

Orthostatic hypotension 1 (MONDO:0009123) is a disease caused by DBH (GenCC Strong), with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include droxidopa, edrophonium, and atropine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DBH (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 444
• Phenotypes (HPO): 28
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001278	Orthostatic hypotension	Very frequent (80-99%)
HP:0001488	Bilateral ptosis	Very frequent (80-99%)
HP:0011979	Elevated urinary dopamine	Very frequent (80-99%)
HP:0012384	Rhinitis	Very frequent (80-99%)
HP:0001279	Syncope	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0003138	Increased blood urea nitrogen	Frequent (30-79%)
HP:0003259	Elevated circulating creatinine concentration	Frequent (30-79%)
HP:0009020	Exercise-induced muscle fatigue	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012877	Retrograde ejaculation	Frequent (30-79%)
HP:0000017	Nocturia	Occasional (5-29%)
HP:0000622	Blurred vision	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0003115	Abnormal EKG	Occasional (5-29%)
HP:0012670	Orthostatic syncope	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Very rare (<1-4%)
HP:0000855	Insulin resistance	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	orthostatic hypotension 1
Mondo ID	MONDO:0009123
MeSH	C535600
OMIM	223360
Orphanet	230
DOID	DOID:0090145
SNOMED CT	237923004
UMLS	C4746777
MedGen	1648402
GARD	0001903
Is cancer (heuristic)	no

Also known as: dopamine beta hydroxylase deficiency · dopamine beta-hydroxylase deficiency · noradrenaline deficiency · norepinephrine deficiency · orthostatic hypotension 1, due to DBH deficiency

Data availability: 444 ClinVar variants · 4 GenCC gene-disease records.

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 biogenic amine metabolism and transport › inborn disorder of neurotransmitter metabolism and transport › disorder of catecholamine synthesis › orthostatic hypotension 1

Related subtypes (1): aromatic L-amino acid decarboxylase 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

444 retrieved; paginated sample, class counts are floors:

193 uncertain significance, 167 likely benign, 31 benign, 26 conflicting classifications of pathogenicity, 9 pathogenic, 9 benign/likely benign, 7 not provided, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1752	NM_000787.3(DBH):c.[301G>A;1033G>A]		Pathogenic	no assertion criteria provided
1750	NM_000787.4(DBH):c.339+2T>C	DBH	Pathogenic	criteria provided, multiple submitters, no conflicts
1982984	NM_000787.4(DBH):c.715A>T (p.Lys239Ter)	DBH	Pathogenic	criteria provided, single submitter
2022460	NM_000787.4(DBH):c.1002C>A (p.Tyr334Ter)	DBH	Pathogenic	criteria provided, single submitter
2423393	NC_000009.11:g.(?136501494)(136505134_?)del	DBH	Pathogenic	criteria provided, single submitter
2757215	NM_000787.4(DBH):c.1239_1242del (p.Thr413_His414insTer)	DBH	Pathogenic	criteria provided, single submitter
2761924	NM_000787.4(DBH):c.945del (p.Gly316fs)	DBH	Pathogenic	criteria provided, single submitter
2897826	NM_000787.4(DBH):c.1499del (p.Leu500fs)	DBH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4708159	NM_000787.4(DBH):c.223C>T (p.Gln75Ter)	DBH	Pathogenic	criteria provided, single submitter
846731	NM_000787.4(DBH):c.468dup (p.Lys157fs)	DBH	Pathogenic	criteria provided, single submitter
3693086	NM_000787.4(DBH):c.1192-1G>A	DBH	Likely pathogenic	criteria provided, single submitter
1378698	NM_000787.4(DBH):c.757G>A (p.Val253Ile)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420176	NM_000787.4(DBH):c.1030A>C (p.Asn344His)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217764	NM_000787.4(DBH):c.1033G>A (p.Asp345Asn)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2457729	NM_000787.4(DBH):c.553G>A (p.Gly185Ser)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365636	NM_000787.4(DBH):c.407T>C (p.Val136Ala)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365647	NM_000787.4(DBH):c.807C>T (p.Cys269=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365648	NM_000787.4(DBH):c.849C>T (p.Cys283=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365651	NM_000787.4(DBH):c.921+8C>T	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365655	NM_000787.4(DBH):c.1025-6T>A	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365657	NM_000787.4(DBH):c.1094T>C (p.Met365Thr)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365659	NM_000787.4(DBH):c.1173G>A (p.Thr391=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365670	NM_000787.4(DBH):c.1599G>A (p.Ala533=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365674	NM_000787.4(DBH):c.1788C>T (p.Cys596=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365675	NM_000787.4(DBH):c.1825G>A (p.Val609Ile)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365677	NM_000787.4(DBH):c.1840G>A (p.Gly614Arg)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
529773	NM_000787.4(DBH):c.1444G>A (p.Gly482Arg)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710801	NM_000787.4(DBH):c.624C>T (p.Pro208=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
714636	NM_000787.4(DBH):c.354C>T (p.Asp118=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718866	NM_000787.4(DBH):c.165G>A (p.Pro55=)	DBH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DBH	Strong	Autosomal recessive	orthostatic hypotension 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DBH	Orphanet:230	Dopamine beta-hydroxylase deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DBH	HGNC:2689	ENSG00000123454	P09172	Dopamine beta-hydroxylase	gencc,clinvar
DBH-AS1	HGNC:24155	ENSG00000225756		DBH antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DBH	Dopamine beta-hydroxylase	Catalyzes the hydroxylation of dopamine to noradrenaline (also known as norepinephrine), and is thus vital for regulation of these neurotransmitters.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DBH	Enzyme (other)	yes	1.14.17.1	Cu2_ascorb_mOase_N, DBH-like, DOMON_domain
DBH-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
liver	1
right adrenal gland	1
cauda epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DBH	146	tissue_specific	marker	right lobe of liver, liver, right adrenal gland
DBH-AS1	161		yes	corpus epididymis, right lobe of liver, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DBH	1,263
DBH-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DBH	P09172	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Catecholamine biosynthesis	1	2855.0×	4e-04	DBH

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
leukocyte mediated immunity	1	16852.0×	7e-04	DBH
regulation of vascular associated smooth muscle cell proliferation	1	16852.0×	7e-04	DBH
octopamine biosynthetic process	1	8426.0×	7e-04	DBH
homoiothermy	1	8426.0×	7e-04	DBH
regulation of vascular endothelial cell proliferation	1	5617.3×	8e-04	DBH
regulation of extrinsic apoptotic signaling pathway	1	3370.4×	0.001	DBH
fear response	1	2808.7×	0.001	DBH
norepinephrine biosynthetic process	1	2106.5×	0.001	DBH
dopamine catabolic process	1	1685.2×	0.002	DBH
behavioral response to ethanol	1	1203.7×	0.002	DBH
maternal behavior	1	1123.5×	0.002	DBH
vasoconstriction	1	887.0×	0.002	DBH
response to pain	1	887.0×	0.002	DBH
leukocyte migration	1	624.1×	0.003	DBH
positive regulation of vasoconstriction	1	601.9×	0.003	DBH
response to amphetamine	1	495.6×	0.003	DBH
blood vessel remodeling	1	383.0×	0.004	DBH
visual learning	1	306.4×	0.004	DBH
memory	1	183.2×	0.006	DBH
locomotory behavior	1	179.3×	0.006	DBH
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	DBH
glucose homeostasis	1	130.6×	0.008	DBH
chemical synaptic transmission	1	77.3×	0.013	DBH

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
DBH	1	3
DBH-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HYPERICIN	3	DBH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DBH	7	Binding:6, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DBH	1.14.17.1	dopamine beta-monooxygenase

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	DBH

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	DBH
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DBH-AS1

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)
DBH-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	5
Not specified	2
PHASE2/PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00581477	PHASE2/PHASE3	TERMINATED	Treatment of Orthostatic Hypotension
NCT00633880	PHASE3	COMPLETED	Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)
NCT00738062	PHASE3	COMPLETED	Open-Label Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)
NCT00782340	PHASE3	COMPLETED	A Clinical Study for Patients With Neurogenic Orthostatic Hypotension (NOH) Using Droxidopa
NCT01132326	PHASE3	COMPLETED	Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (Droxi-304)
NCT01927055	PHASE3	TERMINATED	A Clinical Study of Patients With Symptomatic NOH to Assess Sustained Effects of Droxidopa Therapy
NCT00748059	PHASE1	COMPLETED	The Pathophysiology of Orthostatic Hypotension
NCT00889135	Not specified	APPROVED_FOR_MARKETING	Long Term Treatment With L-DOPS
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DROXIDOPA	4	7
EDROPHONIUM	4	2
ATROPINE	4	1
ISOPROTERENOL	4	1
METHYLDOPA	4	1
METOCLOPRAMIDE	4	1
NITROPRUSSIDE	4	1
PHENYLEPHRINE	4	1
TYRAMINE	3	1
YOHIMBINE	3	1
CHEMBL1593851	0	7
CHEMBL4557433	0	1