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Garrett A, Loveday C, King L, et al. Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. Genet Med. 2021;doi: 10.1016/j.gim.2021.08.004.
Garrett, A., Loveday, C., King, L., Butler, S., Robinson, R., Horton, C., Yussuf, A., Choi, S., Torr, B., Durkie, M., Burghel, G. J., Drummond, J., Berry, I., Wallace, A., Callaway, A., Eccles, D., Tischkowitz, M., Tatton-Brown, K., Snape, K., McVeigh, T., Izatt, L., Woodward, E. R., Burnichon, N., Gimenez-Roqueplo, A. P., Mazzarotto, F., Whiffin, N., Ware, J., Hanson, H., Pesaran, T., LaDuca, H., Buffet, A., Maher, E. R., Turnbull, C. (2021). Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. Genetics in medicine : official journal of the American College of Medical Genetics, . https://doi.org/10.1016/j.gim.2021.08.004
Garrett, Alice, et al. "Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD." Genetics in medicine : official journal of the American College of Medical Genetics vol. (2021). doi: https://doi.org/10.1016/j.gim.2021.08.004
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 AP, Mazzarotto F, Whiffin N, Ware J, Hanson H, Pesaran T, LaDuca H, Buffet A, Maher ER, Turnbull C. Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. Genet Med. 2021 Nov 19; doi: 10.1016/j.gim.2021.08.004. Epub 2021 Nov 19. PMID: 34906457.
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Genet Med. 2021 Nov 19; doi: 10.1016/j.gim.2021.08.004. Epub 2021 Nov 19.

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

Genetics in medicine : official journal of the American College of Medical Genetics

Alice Garrett, Chey Loveday, Laura King, Samantha Butler, Rachel Robinson, Carrie Horton, Amal Yussuf, Subin Choi, Beth Torr, Miranda Durkie, George J Burghel, James Drummond, Ian Berry, Andrew Wallace, Alison Callaway, Diana Eccles, Marc Tischkowitz, Katrina Tatton-Brown, Katie Snape, Terri McVeigh, Louise Izatt, Emma R Woodward, Nelly Burnichon, Anne-Paule Gimenez-Roqueplo, Francesco Mazzarotto, Nicola Whiffin, James Ware, Helen Hanson, Tina Pesaran, Holly LaDuca, Alexandre Buffet, Eamonn R Maher, Clare Turnbull,

Affiliations

  1. Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, United Kingdom.
  2. Central and South Genomic Laboratory Hub, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom.
  3. North East and Yorkshire Genomic Laboratory Hub, Central Lab, The Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
  4. Ambry Genetics, Aliso Viejo, CA.
  5. North East and Yorkshire Genomic Laboratory Hub, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
  6. The Manchester Centre for Genomic Medicine and North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
  7. East Genomic Laboratory Hub, Cambridge University Hospitals Genomic Laboratory, Cambridge University Hospitals, Cambridge, United Kingdom.
  8. Central and South Genomics Laboratory Hub, Wessex Regional Genetics Laboratory, Salisbury Hospital NHS Foundation Trust, Salisbury District Hospital, Salisbury, United Kingdom.
  9. Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
  10. Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; East Anglian Medical Genetics Unit, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom.
  11. St. George's University, London, United Kingdom; Department of Clinical Genetics, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.
  12. Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.
  13. Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
  14. Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), Manchester University NHS Foundation Trust, Manchester, United Kingdom; Division of Evolution and Genomic Sciences, School of Biological Sciences, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, United Kingdom.
  15. University of Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Genetics Department, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
  16. National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, London, United Kingdom.
  17. The Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; The Centre for Personalised Medicine, St Anne's College, University of Oxford, Oxford, United Kingdom.
  18. Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, United Kingdom; Department of Clinical Genetics, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.
  19. Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  20. Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, United Kingdom; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom. Electronic address: [email protected].

PMID: 34906457 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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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

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