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

Abstract

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 SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene 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 (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 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.

Keywords: Cancer; Germline; SDHB; SDHD; Variant interpretation.

Figure 1

Variant position schematic. Lolliplot showing the position of SDHB and SDHD variants in 51,377 controls and 6328 and 5847 cases (of phaeochromocytoma and paraganglioma), respectively. Variants identified in cases are represented by red circles and those in controls are represented by yellow circles with proportional representation for variants identified in both. Exon-exon boundaries are shown with a dashed line. Protein domains are represented by colored blocks. Variant cluster regions (CR), as defined using a custom clustering algorithm (see methods), are shown as black rectangles below each protein (P < .004). Fer_2_3, 2Fe-2S iron-sulfur cluster binding domain (red); Fer4_17, 4Fe-4S dicluster domain (purple); CybS, succinate dehydrogenase cytochrome B small subunit (blue). Escore interspecies conservation is presented.