Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
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Date
2022-01-01Author
Garrett, A
Loveday, C
King, L
Butler, S
Robinson, R
Horton, C
Yussuf, A
Choi, S
Torr, B
Durkie, M
Burghel, GJ
Drummond, J
Berry, I
Wallace, A
Callaway, A
Eccles, D
Tischkowitz, M
Tatton-Brown, K
Snape, K
McVeigh, T
Izatt, L
Woodward, ER
Burnichon, N
Gimenez-Roqueplo, A-P
Mazzarotto, F
Whiffin, N
Ware, J
Hanson, H
Pesaran, T
LaDuca, H
Buffet, A
Maher, ER
Turnbull, C
Cancer Variant Interpretation Group UK (CanVIG-UK),
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cancer Variant Interpretation Group UK (CanVIG-UK)
Research team
Cancer Genetics Education & Quality Improvement
Language
eng
Date accepted
2021-08-10
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2022, 24 (1), pp. 41 - 50
Publisher
ELSEVIER SCIENCE INC