Carney-Stratakis syndrome: genes and variants

Genes linked to Carney-Stratakis syndrome

• SDHD: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial

  It provides a membrane-anchoring component of succinate dehydrogenase and is required for normal complex II electron transfer. Germline loss-of-function variants, often showing a parent-of-origin effect, strongly predispose to head-and-neck paragangliomas and pheochromocytomas.

  11 disease-causing and 182 uncertain variants in SDHD are linked to Carney-Stratakis syndrome.

• SDHB: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial

  It transfers electrons from succinate oxidation through iron-sulfur centers toward ubiquinone in mitochondrial complex II. Heterozygous loss-of-function variants strongly predispose to paraganglioma and pheochromocytoma and can also increase renal-tumor and gastrointestinal-stromal-tumor risk.

  7 disease-causing and 11 uncertain variants in SDHB are linked to Carney-Stratakis syndrome.

• SDHC: Succinate dehydrogenase cytochrome b560 subunit, mitochondrial

  It anchors succinate dehydrogenase to the inner mitochondrial membrane and helps transfer electrons from the catalytic subunits to ubiquinone. Heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and some gastrointestinal stromal tumors.

  2 disease-causing and 1 uncertain variants in SDHC are linked to Carney-Stratakis syndrome.

Where Carney-Stratakis syndrome variants cluster

• SDHD Transmembrane (positions 91–111): 5 of 11 disease-causing changes, 3.4× more than its size predicts.
• SDHB 4Fe-4S ferredoxin-type (positions 176–206): 3 of 7 disease-causing changes, 3.9× more than its size predicts.

Known disease-causing variants in Carney-Stratakis syndrome

Uncertain variants in Carney-Stratakis syndrome that look disease-causing

Which prediction tools work for Carney-Stratakis syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 100 out of 100
• PolyPhen-2: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Pheochromocytoma is also caused by SDHD variants; they fall partly in the same places as the Carney-Stratakis syndrome variants (14 disease-causing).
• Paragangliomas with sensorineural hearing loss is also caused by SDHD variants; they fall partly in the same places as the Carney-Stratakis syndrome variants (13 disease-causing).
• Cowden syndrome is also caused by SDHD variants; they fall partly in the same places as the Carney-Stratakis syndrome variants (11 disease-causing).
• Gastrointestinal stromal tumor is also caused by SDHB variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (53 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHB variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (48 disease-causing).
• Pheochromocytoma is also caused by SDHB variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (47 disease-causing).
• Inherited phaeochromocytoma and paraganglioma excluding NF1 is also caused by SDHB variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (4 disease-causing).
• Gastrointestinal stromal tumor is also caused by SDHC variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (16 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHC variants; they fall mostly in different places as the Carney-Stratakis syndrome variants (16 disease-causing).

Diseases related to Carney-Stratakis syndrome

• Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHB, SDHC and SDHD
• Hereditary pheochromocytoma and paraganglioma, also linked to SDHB, SDHC and SDHD
• Gastrointestinal stromal tumor, also linked to SDHB and SDHC
• Pheochromocytoma, also linked to SDHB and SDHD
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to SDHB and SDHC
• Mitochondrial complex 2 deficiency, nuclear type 3, also linked to SDHB and SDHD
• Cowden syndrome, also linked to SDHD
• Mitochondrial complex II deficiency, nuclear type 1, also linked to SDHD
• Paragangliomas with sensorineural hearing loss, also linked to SDHD

Frequently asked questions

Which genes are linked to Carney-Stratakis syndrome?

In CATVariant, Carney-Stratakis syndrome is linked to 3 analyzed proteins: SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial), SDHB (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial) and SDHC (Succinate dehydrogenase cytochrome b560 subunit, mitochondrial).

How many genetic variants are linked to Carney-Stratakis syndrome?

239 variants: 20 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 194 are of uncertain significance or have conflicting reports.

Which uncertain variants in Carney-Stratakis syndrome look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SDHD G138E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Carney-Stratakis syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 19 disease-causing and 11 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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