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.
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