Carney-Stratakis syndrome

Summary

Carney-Stratakis syndrome (MONDO:0011740) is a disease caused by variants in SDHB, SDHC, and SDHD, with 7 cohort genes and 1 clinical trial. The dominant Reactome pathway is Maturation of TCA enzymes and regulation of TCA cycle (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: SDHB (GenCC Definitive), SDHC (GenCC Strong), SDHD (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 771
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0002668	Paraganglioma	Very frequent (80-99%)
HP:0100723	Gastrointestinal stroma tumor	Very frequent (80-99%)
HP:0000360	Tinnitus	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002239	Gastrointestinal hemorrhage	Frequent (30-79%)
HP:0005214	Intestinal obstruction	Frequent (30-79%)
HP:0006824	Cranial nerve paralysis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Carney-Stratakis syndrome
Mondo ID	MONDO:0011740
MeSH	C564650
OMIM	606864
Orphanet	97286
DOID	DOID:0080533
NCIT	C94831
SNOMED CT	722377004
UMLS	C1847319
MedGen	376098
GARD	0010643
Is cancer (heuristic)	no

Also known as: Carney dyad · Carney-Stratakis dyad · Carney-Stratakis dyad of paraganglioma and gastric stromal sarcoma · Carney-Stratakis syndrome · gist-paraganglioma dyad · paraganglioma and gastric stromal sarcoma · paraganglioma and gastrointestinal stromal tumour · paraganglioma and gist

Data availability: 771 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › polyendocrinopathy › multiple polyglandular tumor › Carney-Stratakis syndrome

Related subtypes (2): Carney triad, multiple endocrine neoplasia

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:

264 uncertain significance, 125 likely benign, 64 benign/likely benign, 61 pathogenic, 49 conflicting classifications of pathogenicity, 26 pathogenic/likely pathogenic, 7 likely pathogenic, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424604	NC_000011.9:g.(?111171709)(111958707_?)del	DIXDC1	Pathogenic	criteria provided, single submitter
1319258	NM_003002.4(SDHD):c.49C>T (p.Arg17Ter)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
1746035	NM_003002.4(SDHD):c.52+1_52+2delinsAA	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
239460	NM_003002.4(SDHD):c.10dup (p.Leu4fs)	LOC126861339	Pathogenic	criteria provided, single submitter
2925495	NM_003002.4(SDHD):c.2T>C (p.Met1Thr)	LOC126861339	Pathogenic	criteria provided, single submitter
3757250	NM_003002.4(SDHD):c.52+1G>T	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
142764	NM_003000.3(SDHB):c.72+1G>T	LOC129929542	Pathogenic/Likely 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
12781	NM_003000.3(SDHB):c.725G>A (p.Arg242His)	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
142637	NM_003000.3(SDHB):c.689G>A (p.Arg230His)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183747	NM_003000.3(SDHB):c.600G>T (p.Trp200Cys)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183793	NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183814	NM_003000.3(SDHB):c.380T>G (p.Ile127Ser)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183925	NM_003000.3(SDHB):c.541-2A>G	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18454	NM_003000.3(SDHB):c.418G>T (p.Val140Phe)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185342	NM_003000.3(SDHB):c.166_170del (p.Pro56fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
186150	NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1916161	NM_003000.3(SDHB):c.637dup (p.Met213fs)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
230243	NM_003000.3(SDHB):c.640C>T (p.Gln214Ter)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29896	NM_003000.3(SDHB):c.423+1G>A	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
3892375	NM_003000.3(SDHB):c.718_719del (p.Leu240fs)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428931	NM_003000.3(SDHB):c.424-1G>A	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183753	NM_003001.5(SDHC):c.397C>T (p.Arg133Ter)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
41776	NM_003001.5(SDHC):c.43C>T (p.Arg15Ter)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
428933	NM_003001.5(SDHC):c.377A>G (p.Tyr126Cys)	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076624	NC_000011.9:g.(?111957547)(111958707_?)del	SDHD	Pathogenic	criteria provided, single submitter
1372650	NM_003002.4(SDHD):c.281_282insAATA (p.Leu95fs)	SDHD	Pathogenic	criteria provided, single submitter
1381354	NC_000011.9:g.(?111957632)(111965694_?)del	SDHD	Pathogenic	criteria provided, single submitter
1401809	NM_003002.4(SDHD):c.317G>A (p.Gly106Asp)	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · Orphanet: 20 · 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	Carney-Stratakis syndrome	16
SDHC	Strong	Autosomal dominant	Carney-Stratakis syndrome	11
SDHD	Strong	Autosomal dominant	Carney-Stratakis syndrome	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
SDHC	Orphanet:139411	Carney triad
SDHC	Orphanet:201	Cowden syndrome
SDHC	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHC	Orphanet:44890	Gastrointestinal stromal tumor
SDHC	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
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	gencc,clinvar
SDHC	HGNC:10682	ENSG00000143252	Q99643	Succinate dehydrogenase cytochrome b560 subunit, mitochondrial	gencc,clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	gencc,clinvar
TIMM8B	HGNC:11818	ENSG00000150779	Q9Y5J9	Mitochondrial import inner membrane translocase subunit Tim8 B	clinvar
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	clinvar
DIXDC1	HGNC:23695	ENSG00000150764	Q155Q3	Dixin	clinvar
HOATZ	HGNC:25061	ENSG00000183644	Q6PI97	Cilia- and flagella-associated protein HOATZ	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).
SDHC	Succinate dehydrogenase cytochrome b560 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).
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).
TIMM8B	Mitochondrial import inner membrane translocase subunit Tim8 B	Probable mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane.
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
DIXDC1	Dixin	Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2.
HOATZ	Cilia- and flagella-associated protein HOATZ	Required for motile ciliogenesis and flagellar genesis by mediating the maturation of the glycolytic enzyme ENO4.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.43

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)	3	5.1×	0.031
Other/Unknown	4	1.0×	0.626

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
SDHC	Enzyme (other)	yes	1.3.5.1	SuccDH_FuR_B_TM-su, Succ_DH_cytb556, Succ_DH_cyt_bsu_CS
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
TIMM8B	Other/Unknown	no		Tim10-like, Tim10-like_dom_sf
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
DIXDC1	Other/Unknown	no		DIX, CH_dom, Dsh/Dvl-rel
HOATZ	Other/Unknown	no		HOATZ-like

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
islet of Langerhans	1
right adrenal gland	1
right adrenal gland cortex	1
jejunal mucosa	1
jejunum	1
rectum	1
cervix squamous epithelium	1
heart right ventricle	1
tongue squamous epithelium	1
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
blood vessel layer	1
calcaneal tendon	1
inferior vagus X ganglion	1
bronchial epithelial cell	1
olfactory segment of nasal mucosa	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
SDHC	134	ubiquitous	marker	islet of Langerhans, right adrenal gland cortex, right adrenal gland
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
TIMM8B	288	ubiquitous	marker	tongue squamous epithelium, heart right ventricle, cervix squamous epithelium
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
DIXDC1	283	ubiquitous	marker	calcaneal tendon, blood vessel layer, inferior vagus X ganglion
HOATZ	129	tissue_specific	marker	right uterine tube, bronchial epithelial cell, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHB	5,471
SDHC	5,278
SDHD	2,229
HOATZ	1,818
TIMM8B	1,579
ALG9	1,167
DIXDC1	782

Intra-cohort edges

A	B	Sources
SDHB	SDHC	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction
SDHB	TIMM8B	string_interaction
SDHC	SDHD	biogrid_interaction, intact, string_interaction
SDHC	TIMM8B	string_interaction
SDHD	TIMM8B	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SDHB	P21912	6
SDHC	Q99643	2
SDHD	O14521	2
ALG9	Q9H6U8	2
DIXDC1	Q155Q3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMM8B	Q9Y5J9	93.60
HOATZ	Q6PI97	74.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of TCA enzymes and regulation of TCA cycle	3	342.6×	7e-07	SDHB, SDHC, SDHD
Citric acid cycle (TCA cycle)	3	253.8×	9e-07	SDHB, SDHC, SDHD
Respiratory electron transport	3	57.1×	6e-05	SDHB, SDHC, SDHD
Defective ALG9 causes CDG-1l	1	2284.0×	0.002	ALG9
Aerobic respiration and respiratory electron transport	2	35.4×	0.004	SDHB, SDHC
Diseases associated with N-glycosylation of proteins	1	126.9×	0.020	ALG9
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	41.5×	0.051	ALG9
Mitochondrial protein import	1	33.6×	0.055	TIMM8B
Diseases of glycosylation	1	26.2×	0.063	ALG9
Diseases of metabolism	1	16.1×	0.085	ALG9
Metabolism	2	4.7×	0.085	SDHB, SDHC
Asparagine N-linked glycosylation	1	12.0×	0.101	ALG9
Post-translational protein modification	1	3.8×	0.271	ALG9
Disease	1	2.6×	0.344	ALG9
Metabolism of proteins	1	2.5×	0.344	ALG9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, succinate to ubiquinone	3	1444.5×	1e-08	SDHB, SDHC, SDHD
tricarboxylic acid cycle	3	218.9×	3e-06	SDHB, SDHC, SDHD
proton motive force-driven mitochondrial ATP synthesis	3	112.8×	2e-05	SDHB, SDHC, SDHD
regulation of catecholamine secretion	1	2407.4×	0.002	SDHD
aerobic respiration	2	70.8×	0.002	SDHB, SDHC
forebrain ventricular zone progenitor cell division	1	802.5×	0.005	DIXDC1
succinate metabolic process	1	481.5×	0.008	SDHB
cerebral cortex radially oriented cell migration	1	240.7×	0.013	DIXDC1
modification of postsynaptic actin cytoskeleton	1	200.6×	0.014	DIXDC1
protein insertion into mitochondrial inner membrane	1	185.2×	0.014	TIMM8B
dolichol-linked oligosaccharide biosynthetic process	1	120.4×	0.018	ALG9
respiratory electron transport chain	1	120.4×	0.018	SDHB
obsolete protein targeting to mitochondrion	1	83.0×	0.022	TIMM8B
axoneme assembly	1	77.7×	0.022	HOATZ
regulation of microtubule cytoskeleton organization	1	77.7×	0.022	DIXDC1
positive regulation of Wnt signaling pathway	1	54.7×	0.029	DIXDC1
negative regulation of neuron differentiation	1	38.8×	0.038	DIXDC1
protein N-linked glycosylation	1	37.6×	0.038	ALG9
regulation of actin cytoskeleton organization	1	22.5×	0.058	DIXDC1
canonical Wnt signaling pathway	1	21.9×	0.058	DIXDC1
cellular response to hypoxia	1	17.3×	0.069	SDHD
flagellated sperm motility	1	16.7×	0.069	HOATZ
sensory perception of sound	1	14.4×	0.076	TIMM8B
cilium assembly	1	10.5×	0.099	HOATZ
protein transport	1	6.3×	0.155	TIMM8B
spermatogenesis	1	5.0×	0.183	HOATZ

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 1 of 7 evidence-associated genes (14%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHB	0	0
SDHC	0	0
SDHD	0	0
TIMM8B	0	0
ALG9	0	0
DIXDC1	0	0
HOATZ	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
SDHB	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
SDHC	1.3.5.1	succinate dehydrogenase
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	3	SDHB, SDHC, ALG9
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SDHD, TIMM8B, DIXDC1, HOATZ

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHB	4	—
SDHC	0	—
SDHD	0	—
TIMM8B	0	—
ALG9	0	—
DIXDC1	0	—
HOATZ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients