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 SDHAF2 and SDHAF2 associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) (Paraganglioma 2, MIM: 601650). SDHAF2 was first reported in relation to PGL/PCC in 2009 [Hao et al., PMID: 19628817]. SDHAF2 related hereditary PGL/PCC syndromes are rare and only account for less than 0.1% of the cases with PGL/PCC. A Dutch founder variant in exon 2 of SDHAF2 gene, NM_017841.2(SDHAF2):c.232G>A (p.Gly78Arg), was identified in a large Dutch family via linkage study over a 30 years of period, which showed a parent-of-origin effect [PMIDs: 19628817, 6286462, 7814027, 8388849, 21224366]. Evidence suggests that this pathogenic variant in exon 2 of SDHAF2 destabilizes the protein, impairing its interaction with SDHA [PMID: 19628817]. This variant was also reported in a small Spanish family [PMID: 20071235], and sporadic cases [PMID: 28384794]. A variant at the same codon, but with different nucleotide change, NM_017841.4:c.232G>C p.Gly78Arg, was reported in a sporadic case from a cohort of 79 patients [PMID: 22241717]. Another missense variant and three nonsense variants are included in this curation [PMIDs: 26096992, 26269449, 22241717]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence is mainly from a comprehensive study on the p.Gly78Arg Dutch founder variant [PMID: 19628817]. The SDHA flavination was decreased which results from impaired interaction with SDHA in patients’ tumor cells. In yeast model, wt hSDHAF2 can rescue growth defects by increasing the falvination in the model with yeast sdh5 deletion, but this missense variant had no such rescuing effect. Other studies in yeast also indicated mutations in yeast sdh5 disrupt the covalent flavination of sdh1 [PMID: 23062074]. In summary, SDHAF2 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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