Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD

Purpose: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. Methods: We compared the frequency of SDHBand SDHDvery rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pangene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. Results: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (alpha alpha 177-260, P =.001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (alpha alpha 70-114, P =.000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). Conclusion: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Automated summary

The weight of evidence for the observation of rare missense variants in SDHB or SDHD in individuals with rare neuroendocrine tumors is uncertain. This study compared the frequency of these variants in cases of pheochromocytomas and paragangliomas (PCC/PGL) with population controls and calculated likelihood ratios for their pathogenicity. Regional enrichments of these variants and subphenotypic likelihood ratios were also measured. The study found that these rare missense variants can provide substantial evidence toward pathogenicity in PCC/PGL.