Pheochromocytoma/paraganglioma syndrome 4

Summary

Pheochromocytoma/paraganglioma syndrome 4 (MONDO:0007273) is a disease caused by SDHB (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Citric acid cycle (TCA cycle) (4 cohort genes).

At a glance

• Causal gene: SDHB (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,326

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pheochromocytoma/paraganglioma syndrome 4
Mondo ID	MONDO:0007273
OMIM	115310
DOID	DOID:0061219
UMLS	C1861848
MedGen	349380
GARD	0010546
Is cancer (heuristic)	no

Also known as: carotid body tumours and multiple extraadrenal Pheochromocytomas · paraganglioma caused by mutation in SDHB · paragangliomas 4 · paragangliomas type 4 · PGL4 · pheochromocytoma, extraadrenal and cervical paraganglioma · pheochromocytoma/paraganglioma syndrome 4 · SDHB paraganglioma · SDHB-related hereditary paraganglioma-pheochromocytoma syndrome · SDHB-related tumor predisposition

Data availability: 1,326 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › pheochromocytoma/paraganglioma syndrome 4

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

600 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 184 likely benign, 66 pathogenic, 42 benign/likely benign, 35 pathogenic/likely pathogenic, 29 conflicting classifications of pathogenicity, 22 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
239419	NC_000001.11:g.(?17018722)(17054170_?)del	LOC129929541	Pathogenic	criteria provided, single submitter
142764	NM_003000.3(SDHB):c.72+1G>T	LOC129929542	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684628	Single allele	LOC129929542	Pathogenic	criteria provided, single submitter
18455	NC_000001.10:g.17375249_17390927del15679	LOC129929542	Pathogenic	no assertion criteria provided
18456	NC_000001.10:g.17376556_17396932del20377	LOC129929542	Pathogenic	no assertion criteria provided
1065988	NM_003000.3(SDHB):c.200+1G>C	SDHB	Pathogenic	criteria provided, single submitter
1066038	NM_003000.3(SDHB):c.424-2A>G	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066588	NM_003000.3(SDHB):c.557G>A (p.Cys186Tyr)	SDHB	Pathogenic	criteria provided, single submitter
1069440	NM_003000.3(SDHB):c.412del (p.Asp138fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1070347	NM_003000.3(SDHB):c.466del (p.Tyr156fs)	SDHB	Pathogenic	criteria provided, single submitter
1072115	NM_003000.3(SDHB):c.765+1G>A	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072823	NC_000001.10:g.(?17345376)(17345463_?)del	SDHB	Pathogenic	criteria provided, single submitter
1072824	NC_000001.10:g.(?17345376)(17371403_?)del	SDHB	Pathogenic	criteria provided, single submitter
1074491	NM_003000.3(SDHB):c.17_18insACTCTCCTTGAGGCGCCGGTTGC (p.Ala15fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12778	NM_003000.3(SDHB):c.268C>T (p.Arg90Ter)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12779	NM_003000.3(SDHB):c.590C>G (p.Pro197Arg)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12781	NM_003000.3(SDHB):c.725G>A (p.Arg242His)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12782	NM_003000.3(SDHB):c.716_719del (p.Ser239fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12783	NM_003000.3(SDHB):c.79C>T (p.Arg27Ter)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12784	NM_003000.3(SDHB):c.(-151_-1)_(72+1_73-1)del	SDHB	Pathogenic	no assertion criteria provided
12785	NM_003000.3(SDHB):c.136C>G (p.Arg46Gly)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12787	NM_003000.3(SDHB):c.395A>C (p.His132Pro)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12790	NM_003000.3(SDHB):c.423+1G>C	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1285202	NM_003000.3(SDHB):c.200+1G>A	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1326294	NM_003000.3(SDHB):c.423+1G>T	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1362479	NC_000001.10:g.(?17345376)(17359650_?)del	SDHB	Pathogenic	criteria provided, single submitter
1363102	NM_003000.3(SDHB):c.598del (p.Trp200fs)	SDHB	Pathogenic	criteria provided, single submitter
1371694	NM_003000.3(SDHB):c.445_446dup (p.Gln149fs)	SDHB	Pathogenic	criteria provided, single submitter
1380234	NM_003000.3(SDHB):c.183T>A (p.Tyr61Ter)	SDHB	Pathogenic	criteria provided, single submitter
1381081	NM_003000.3(SDHB):c.19_41dup (p.Pro14_Ala15insSerProTer)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 22 · 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
SDHB	Definitive	Autosomal dominant	pheochromocytoma/paraganglioma syndrome 4	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHB	Orphanet:139411	Carney triad
SDHB	Orphanet:201	Cowden syndrome
SDHB	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHB	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHB	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:44890	Gastrointestinal stromal tumor
SDHB	Orphanet:97286	Carney-Stratakis syndrome
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
SDHD	Orphanet:100093	Carcinoid syndrome
SDHD	Orphanet:201	Cowden syndrome
SDHD	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHD	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHD	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHD	Orphanet:97286	Carney-Stratakis syndrome
FH	Orphanet:24	Fumaric aciduria
FH	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
FH	Orphanet:523	Hereditary leiomyomatosis and renal cell cancer

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	gencc,clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	clinvar
FH	HGNC:3700	ENSG00000091483	P07954	Fumarate hydratase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHB	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHD	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
FH	Fumarate hydratase, mitochondrial	Catalyzes the reversible stereospecific interconversion of fumarate to L-malate.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
FH	Enzyme (other)	yes	4.2.1.2	Fumarate_lyase_fam, Fum_hydII, L-Aspartase-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
cardiac ventricle	2
heart left ventricle	2
mucosa of transverse colon	1
jejunal mucosa	1
jejunum	1
rectum	1
body of tongue	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
FH	292	ubiquitous	marker	heart right ventricle, body of tongue, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
SDHB	5,471
FH	3,709
SDHD	2,229

Intra-cohort edges

A	B	Sources
FH	SDHA	string_interaction
FH	SDHB	string_interaction
FH	SDHD	string_interaction
SDHA	SDHB	biogrid_interaction, intact, string_interaction
SDHA	SDHD	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FH	P07954	7
SDHB	P21912	6
SDHA	P31040	5
SDHD	O14521	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Citric acid cycle (TCA cycle)	4	423.0×	1e-10	SDHB, SDHA, SDHD, FH
Maturation of TCA enzymes and regulation of TCA cycle	3	428.2×	6e-08	SDHB, SDHA, SDHD
Respiratory electron transport	3	71.4×	9e-06	SDHB, SDHA, SDHD
Aerobic respiration and respiratory electron transport	2	44.3×	0.001	SDHB, SDHA
Mitochondrial protein degradation	1	28.6×	0.039	FH
Metabolism	2	5.8×	0.039	SDHB, SDHA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tricarboxylic acid cycle	4	510.7×	2e-10	SDHB, SDHA, SDHD, FH
mitochondrial electron transport, succinate to ubiquinone	3	2527.8×	5e-10	SDHB, SDHA, SDHD
proton motive force-driven mitochondrial ATP synthesis	3	197.5×	1e-06	SDHB, SDHA, SDHD
succinate metabolic process	2	1685.2×	2e-06	SDHB, SDHA
respiratory electron transport chain	2	421.3×	3e-05	SDHB, SDHA
fumarate metabolic process	1	4213.0×	6e-04	FH
regulation of catecholamine secretion	1	4213.0×	6e-04	SDHD
obsolete regulation of arginine metabolic process	1	2106.5×	0.001	FH
arginine metabolic process	1	601.9×	0.004	FH
malate metabolic process	1	468.1×	0.004	FH
urea cycle	1	324.1×	0.005	FH
positive regulation of double-strand break repair via nonhomologous end joining	1	247.8×	0.006	FH
homeostasis of number of cells within a tissue	1	110.9×	0.013	FH
aerobic respiration	1	62.0×	0.022	SDHB
positive regulation of cold-induced thermogenesis	1	40.9×	0.031	FH
cellular response to hypoxia	1	30.3×	0.039	SDHD
DNA repair	1	16.0×	0.068	FH
DNA damage response	1	13.4×	0.077	FH
nervous system development	1	11.5×	0.084	SDHA

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHA	1	4
SDHB	0	0
SDHD	0	0
FH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SDHB	4	Binding:4
SDHA	3	Binding:3
FH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
FH	4.2.1.2	fumarate hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
LINEZOLID	4	SDHA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SDHA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	SDHB, FH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SDHD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHB	4	SDHA
SDHD	0	SDHA
FH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.