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. 2024 Feb;26(2):101029.
doi: 10.1016/j.gim.2023.101029. Epub 2023 Nov 17.

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

Angharad M Roberts  1 , Marina T DiStefano  2 , Erin Rooney Riggs  3 , Katherine S Josephs  4 , Fowzan S Alkuraya  5 , Joanna Amberger  6 , Mutaz Amin  7 , Jonathan S Berg  8 , Fiona Cunningham  9 , Karen Eilbeck  10 , Helen V Firth  11 , Julia Foreman  12 , Ada Hamosh  6 , Eleanor Hay  13 , Sarah Leigh  14 , Christa L Martin  15 , Ellen M McDonagh  16 , Daniel Perrett  9 , Erin M Ramos  17 , Peter N Robinson  18 , Ana Rath  7 , David W Sant  10 , Zornitza Stark  19 , Nicola Whiffin  20 , Heidi L Rehm  21 , James S Ware  22
Affiliations

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

Angharad M Roberts et al. Genet Med. 2024 Feb.

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 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. Gene Curation Coalition 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.

Keywords: Allelic requirement; Disease mechanisms; Gene curation; Inheritance modes; Ontology.

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Conflict of interest statement

Conflict of Interest James S. Ware has received research support or consultancy fees from Myokardia, Bristol-Myers Squibb, Pfizer, and Foresite Labs. All other authors declare no conflicts of interest. For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising.

Figures

Figure 1
Figure 1. Process for developing and testing the terminology.
HPO, human phenotype ontology; GenCC, The Gene Curation Coalition; SO, Sequence Ontology.
Figure 2
Figure 2. Matrix of 6 new high-level predicted functional consequences mapped to SO structural consequence terms via a semi-quantitative scale indicating likelihood of each high-level consequence. The semi-quantitative scale is characterized from first principles by expert evaluation.
NMD, nonsense-mediated-decay; UTR, untranslated regions; SO, Sequence Ontology.
See this image and copyright information in PMC

Update of

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