Inheritance

Autosomal dominant

Prevalence

 1-9 / 1 000 000

Source: ORPHA:29072

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer, accessed 07.07.2023

Clinical Validity Scoring Notes and points

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas, pheochromocytomas and gastrointestinal stromal tumors (GIST) including malignant PCC/PGLs transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, as well as stabilization of the SDH complex. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, for SDHB, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability for tumor risk. Therefore, this is a lumping curation for SDHB and SDHB associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 4 (MIM: 115310), Gastrointestinal stromal tumor (MIM: 606764) and Pheochromocytoma (MIM: 171300). SDHB encodes the iron sulfur protein, one of the five subunits of SDH (succinate dehydrogenase), a component of complex II in mitochondria. SDHB was first reported in relation to PGL/PCC in 2001 [Astuti et al., PMID: 11404820]. Pathogenic variants in SDHB including frameshift, nonsense, missense (e.g. p.Pro197Arg, p.Val140Phe and p.Arg242His), splice site and large (exon) deletion variants were reported in the literature with incomplete penetrance and variable expressivity [PIMDs: 19389109, 19802898 and 25827221]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There is extensive experiment evidence including reduced or absent SDHB protein expression [PMID:19576851], reduced enzyme activity [PMID:22835832], increased succinate level, the hallmark of tumorigenesis in PGL and PCC, and increased nuclear expression of HIF1α (hypoxia inducible factor 1α) [PMID:15987702] in tumor cells of patients who carry germline SDHB variants. However, the knockout mouse homolog of human SDHB is homozygous-lethal [PMID 27626380]. In summary, the SDHB gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Source: ClinGen Hereditary Cancer, accessed 07.07.2023

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer, accessed 07.07.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer, accessed 07.07.2023

Molecular Mechanism

Loss of function

Source: ClinGen Hereditary Cancer, accessed 07.07.2023. PMIDs: 19576851, 22835832, 19802898)

Penetrance

(list source/PMID)

Reduced

Source: PMID: 28374168, 29386252

Age of Onset

(list source/PMID)

Adolescence to adulthood

Source: PMID: 28374168, 29386252

Severity

Moderate

Clinical Features

• Multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma and/or a family history.

  • Paragangliomas that arise from neuroendocrine tissue, distributed from the skull base to the pelvic floor.

  • Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. They typically lead to catecholemine excess.

  • Note: Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory.

• Symptoms of PGL/PCC result from effects of catecholamine hypersecretion (sustained or paroxysmal elvations in blood pressure, headach, episodic profuse sweating, forceful palpitations, pallor, and anxiety), palpable abdominal mass, enlarging mass of the skull base/neck, compromise of cranial nerves presenting as hoarseness, dysphagia, soft palate paresis, Horner syndrome; tinnitis.

• Gastrointestinal stromal tumors (GISTs) may also be observed.

Sources: PMID: 20301715

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

The SDHB gene is associated with autosomal dominant hereditary pheochromocytoma-paraganglioma, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715). It has also been associated with autosomal recessive mitochondrial disease, which is characterized by hypotonia, leukoencephalopathy, developmental regression, and complex II deficiency on muscle biopsy (PMID: 22972948, 26642834).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 07.07.2023