Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD
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 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.
Cancer, Germline, SDHB, SDHD, Variant interpretation
41-50
Garrett, A
d8fcdea3-8231-4d5e-8ada-4f932ca1a0c3
Loveday, C
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King, L
ca67081e-4a76-4438-b430-81d324d53307
Butler, S
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Robinson, R
b81f9f32-b468-451d-959b-355aa680f7fb
Horton, C
75285fa1-481a-42e5-9722-2a50ecffd35b
et al.,
96c90377-641f-4276-9d09-6968e3f36258
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Turnbull, Clare
63408861-754b-4f55-a010-29d1bea914e2
5 January 2022
Garrett, A
d8fcdea3-8231-4d5e-8ada-4f932ca1a0c3
Loveday, C
bed064d6-13e9-4429-b847-5ecaaf3f5e19
King, L
ca67081e-4a76-4438-b430-81d324d53307
Butler, S
dfee5666-c5ab-455e-b931-6025138bdb6a
Robinson, R
b81f9f32-b468-451d-959b-355aa680f7fb
Horton, C
75285fa1-481a-42e5-9722-2a50ecffd35b
et al.,
96c90377-641f-4276-9d09-6968e3f36258
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Turnbull, Clare
63408861-754b-4f55-a010-29d1bea914e2
Garrett, A, Loveday, C, King, L, Butler, S, Robinson, R, Horton, C, et al., , Eccles, Diana and Turnbull, Clare
(2022)
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
Genetics in Medicine, 24 (1), .
(doi: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.
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Accepted/In Press date: 10 August 2021
e-pub ahead of print date: 30 November 2021
Published date: 5 January 2022
Additional Information:
Funding Information:
A.G., C.L., L.K., B.T., S.C., and H.H. are supported by CRUK Catalyst Award CanGene-CanVar (C61296/A27223). N.W. is currently supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 220134/Z/20/Z). J.W. is funded by the Wellcome Trust (107469/Z/15/Z), the Medical Research Council (UK), the British Heart Foundation (RE/18/4/34215), and the NIHR Imperial College Biomedical Research Centre. E.R.W. is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).
Publisher Copyright:
© 2021 The Authors
Keywords:
Cancer, Germline, SDHB, SDHD, Variant interpretation
Identifiers
Local EPrints ID: 454515
URI: http://eprints.soton.ac.uk/id/eprint/454515
ISSN: 1098-3600
PURE UUID: 57a3387e-5126-4c8f-90c9-e3f5059dda6f
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Date deposited: 15 Feb 2022 17:30
Last modified: 17 Mar 2024 02:36
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Author:
A Garrett
Author:
C Loveday
Author:
L King
Author:
S Butler
Author:
R Robinson
Author:
C Horton
Author:
et al.
Author:
Clare Turnbull
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