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[Preprint]. 2023 Apr 3:2023.03.30.23287948.

doi: 10.1101/2023.03.30.23287948.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms

Angharad M Roberts^{1

2}, Marina T DiStefano³, Erin Rooney Riggs⁴, Katherine S Josephs^{1

5}, Fowzan S Alkuraya⁶, Joanna Amberger⁷, Mutaz Amin⁸, Jonathan S Berg⁹, Fiona Cunningham¹⁰, Karen Eilbeck¹¹, Helen V Firth^{12

13}, Julia Foreman^{13

10}, Ada Hamosh⁷, Eleanor Hay², Sarah Leigh¹⁴, Christa L Martin¹⁵, Ellen M McDonagh^{10

16}, Daniel Perrett¹⁰, Erin M Ramos¹⁷, Peter N Robinson¹⁸, Ana Rath⁸, David van Sant¹¹, Zornitza Stark^{19

20

21}, Nicola Whiffin^{3

22}, Heidi L Rehm^{3

23}, James S Ware^{1

3

10}

Affiliations

¹ National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London, UK.
² Dept of Medical Genetics, Great Ormond Street Hospital, Great Ormond Street, London. WC1N 3JH, UK.
³ Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Geisinger Autism & Developmental Medicine Institute, Danville, PA, USA.
⁵ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
⁶ Department of Translational Genomics, Center for Genomic Medicine, KFSHRC, Riyadh, Saudi Arabia.
⁷ Online Mendelian Inheritance in Man (OMIM), Johns Hopkins University School of Medicine, USA.
⁸ INSERM, US14-Orphanet, Paris, France.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill NC, 27599.
¹⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, United Kingdom.
¹¹ Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah.
¹² Dept of Medical Genetics, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
¹³ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
¹⁴ Genomics England, Queen Mary University of London, Dawson Hall, London, EC1M 6BQ, UK.
¹⁵ Clinical Genome Resource (ClinGen), USA.
¹⁶ Open Targets, Cambridge, UK.
¹⁷ National Human Genome Research Institute, National Institutes of Health, USA.
¹⁸ The Jackson Laboratory for Genomic Medicine, Farmington CT 06032, USA.
¹⁹ Australian Genomics, Melbourne 3052, Australia.
²⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne 3052, Australia.
²¹ University of Melbourne, Melbourne 3052, Australia.
²² Big Data Institute and Wellcome Centre for Human Genetics, University of Oxford, UK.
²³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

PMID: 37066232
PMCID: PMC10104222
DOI: 10.1101/2023.03.30.23287948

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms

Angharad M Roberts et al. medRxiv. 2023.

[Preprint]. 2023 Apr 3:2023.03.30.23287948.

doi: 10.1101/2023.03.30.23287948.

Authors

Affiliations

¹ National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London, UK.
² Dept of Medical Genetics, Great Ormond Street Hospital, Great Ormond Street, London. WC1N 3JH, UK.
³ Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Geisinger Autism & Developmental Medicine Institute, Danville, PA, USA.
⁵ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
⁶ Department of Translational Genomics, Center for Genomic Medicine, KFSHRC, Riyadh, Saudi Arabia.
⁷ Online Mendelian Inheritance in Man (OMIM), Johns Hopkins University School of Medicine, USA.
⁸ INSERM, US14-Orphanet, Paris, France.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill NC, 27599.
¹⁰ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, United Kingdom.
¹¹ Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah.
¹² Dept of Medical Genetics, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
¹³ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
¹⁴ Genomics England, Queen Mary University of London, Dawson Hall, London, EC1M 6BQ, UK.
¹⁵ Clinical Genome Resource (ClinGen), USA.
¹⁶ Open Targets, Cambridge, UK.
¹⁷ National Human Genome Research Institute, National Institutes of Health, USA.
¹⁸ The Jackson Laboratory for Genomic Medicine, Farmington CT 06032, USA.
¹⁹ Australian Genomics, Melbourne 3052, Australia.
²⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne 3052, Australia.
²¹ University of Melbourne, Melbourne 3052, Australia.
²² Big Data Institute and Wellcome Centre for Human Genetics, University of Oxford, UK.
²³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

PMID: 37066232
PMCID: PMC10104222
DOI: 10.1101/2023.03.30.23287948

Update in

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.
Roberts AM, DiStefano MT, Riggs ER, Josephs KS, Alkuraya FS, Amberger J, Amin M, Berg JS, Cunningham F, Eilbeck K, Firth HV, Foreman J, Hamosh A, Hay E, Leigh S, Martin CL, McDonagh EM, Perrett D, Ramos EM, Robinson PN, Rath A, Sant DW, Stark Z, Whiffin N, Rehm HL, Ware JS. Roberts AM, et al. Genet Med. 2024 Feb;26(2):101029. doi: 10.1016/j.gim.2023.101029. Epub 2023 Nov 17. Genet Med. 2024. PMID: 37982373 Free PMC article.

Abstract

Purpose: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.

Methods: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated.

Results: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources.

Conclusion: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

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Figures

**Fig 1**
Process for developing and testing the terminology

See this image and copyright information in PMC

References

1. Chong J.X. et al. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. Am J Hum Genet 97, 199–215 (2015). - PMC - PubMed
1. Richards S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 17, 405–24 (2015). - PMC - PubMed
1. Riggs E.R. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22, 245–257 (2020). - PMC - PubMed
1. Bean L.J.H. et al. Diagnostic gene sequencing panels: from design to report-a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med 22, 453–461 (2020). - PubMed
1. Strande N.T. et al. Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource. Am J Hum Genet 100, 895–906 (2017). - PMC - PubMed

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This is a preprint.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms

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Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms

Authors

Affiliations

Update in

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