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Quantifying evidence towards pathogenicity for rare phenotypes: the case of succinate dehydrogenase genes SDHB and SDHD

Quantifying evidence towards pathogenicity for rare phenotypes: the case of succinate dehydrogenase genes SDHB and SDHD
Quantifying evidence towards pathogenicity for rare phenotypes: the case of succinate dehydrogenase genes SDHB and SDHD
Purpose: the weight of evidence is uncertain to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumours phaeochromocytomas and paragangliomas (PCC/PGL). Methods: we compared the frequency of SDHB/SDHD very rare missense variants (VRMVs) in 6328/5847 cases of PCC/PGL to population controls to generate a Pan-Gene-Very-Rare-Missense-Variant-Likelihood-Ratio (PG-VRMV-LR). Via windowing analysis we measured regional enrichments of VRMVs to calculate the “Domain-Specific-Very-Rare-Missense-Variant-Likelihood-Ratio” (DS-VRMV-LR). We also calculated subphenotypic likelihood ratios (SP-LRs) for variant pathogenicity for various clinical, histological and molecular features. Results: we estimated the PG-VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed a region of SDHB (ɑɑ 177-260, p=001) for which DS-VRMV-LR was 127.2 (64.9-249.4) and for SDHD the enriched region (ɑɑ 70-114, p=0.000003) yielded a DS-VRMV-LR of 33.9 (14.8-77.8). SP-LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumours (SDHD), positive family history, loss of SDHB staining on immunohistochemistry and succinate:fumarate ratio >97 (SDHB, SDHD). Conclusions: using methodology generaliseable to other gene-phenotype dyads, the likelihood ratios relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence towards pathogenicity.
Cancer, Germline, SDHB, SDHD, Variant interpretation
1098-3600
41-50
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
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 towards pathogenicity for rare phenotypes: the case of succinate dehydrogenase genes SDHB and SDHD. Genetics in Medicine, 24 (1), 41-50. (doi:10.1016/j.gim.2021.08.004).

Record type: Article

Abstract

Purpose: the weight of evidence is uncertain to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumours phaeochromocytomas and paragangliomas (PCC/PGL). Methods: we compared the frequency of SDHB/SDHD very rare missense variants (VRMVs) in 6328/5847 cases of PCC/PGL to population controls to generate a Pan-Gene-Very-Rare-Missense-Variant-Likelihood-Ratio (PG-VRMV-LR). Via windowing analysis we measured regional enrichments of VRMVs to calculate the “Domain-Specific-Very-Rare-Missense-Variant-Likelihood-Ratio” (DS-VRMV-LR). We also calculated subphenotypic likelihood ratios (SP-LRs) for variant pathogenicity for various clinical, histological and molecular features. Results: we estimated the PG-VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed a region of SDHB (ɑɑ 177-260, p=001) for which DS-VRMV-LR was 127.2 (64.9-249.4) and for SDHD the enriched region (ɑɑ 70-114, p=0.000003) yielded a DS-VRMV-LR of 33.9 (14.8-77.8). SP-LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumours (SDHD), positive family history, loss of SDHB staining on immunohistochemistry and succinate:fumarate ratio >97 (SDHB, SDHD). Conclusions: using methodology generaliseable to other gene-phenotype dyads, the likelihood ratios relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence towards 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: Acknowledgments 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).
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
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 15 Feb 2022 17:30
Last modified: 28 Apr 2022 01:35

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Contributors

Author: A Garrett
Author: C Loveday
Author: L King
Author: S Butler
Author: R Robinson
Author: C Horton
Author: et al.
Author: Diana Eccles ORCID iD
Author: Clare Turnbull

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