Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
View / Open Files
Authors
Garrett, Alice
Loveday, Chey
King, Laura
Butler, Samantha
Robinson, Rachel
Horton, Carrie
Yussuf, Amal
Choi, Subin
Torr, Beth
Durkie, Miranda
Burghel, George J
Drummond, James
Berry, Ian
Wallace, Andrew
Callaway, Alison
Eccles, Diana
Tatton-Brown, Katrina
Snape, Katie
McVeigh, Terri
Izatt, Louise
Woodward, Emma R
Burnichon, Nelly
Gimenez-Roqueplo, Anne-Paule
Mazzarotto, Francesco
Whiffin, Nicola
Ware, James
Hanson, Helen
Pesaran, Tina
LaDuca, Holly
Buffet, Alexandre
Maher, Eamonn R
Turnbull, Clare
Cancer Variant Interpretation Group UK (CanVIG-UK)
Publication Date
2022-01Journal Title
Genet Med
ISSN
1098-3600
Publisher
Elsevier BV
Volume
24
Issue
1
Pages
41-50
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Garrett, A., Loveday, C., King, L., Butler, S., Robinson, R., Horton, C., Yussuf, A., et al. (2022). Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.. Genet Med, 24 (1), 41-50. https://doi.org/10.1016/j.gim.2021.08.004
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
Identifiers
External DOI: https://doi.org/10.1016/j.gim.2021.08.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334793
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk