Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems 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, and stabilization of the SDH complex. This is a curation for SDHA and SDHA associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) with autosomal dominant inheritance (Paraganglioma 5, MIM: 614165). The autosomal recessive inherited Leigh syndrome (MIM: 256000), Cardiomyopathy, dilated, 1GG (MIM: 613642) and Mitochondrial Respiratory Chain Complex II deficiency (MIM: 252011) will be curated separately. SDHA encodes the flavoprotein subunit of the SDH-complex (succinate dehydrogenase). SDHA was first reported in relation to PGL/PCC in 1995 [Bourgeron et al., PMID: 7550341]. Germline loss-of-function mutations of SDHA gene have been described in only 3-7% of the patients with PGL/PCCs, in which most pathogenic variants are associated with very low disease penetrance, ranging from 0.1-4.9% [PMID: 29978154]. An initiation codon, two missense, four nonsense and two small deletion variants are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. Absence of SDHA staining specifically associated with SDHA germline mutation in PGL/PCC tumors was demonstrated in 6 cases with 6 germline variants [PMID: 23282968]. Yeast models with null Sdh1 and Arg582Trp Sdh1 mutants showed loss of SDH1 due to instability of the mutant protein. SDHB protein, the catalytic component, is lost in the SDHA mutant patient’s fresh adrenal paraganglioma tumor. WT yeast SDH1 can rescue the deficient growth of null Sdh1 mutant on minimal glycerol/ethanol but the yeast Arg582Trp Sdh1 mutant can not [PMID: 20484225]. In summary, the SDHA gene is definitely associated with autosomal dominant HPGL/PCC with low penetrance. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.
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