Document Type
Article
Publication Date
2-1-2024
Original Citation
Roberts A,
DiStefano M,
Riggs E,
Josephs K,
Alkuraya F,
Amberger J,
Amin M,
Berg J,
Cunningham F,
Eilbeck K,
Firth H,
Foreman J,
Hamosh A,
Hay E,
Leigh S,
Martin C,
McDonagh E,
Perrett D,
Ramos E,
Robinson P,
Rath A,
Sant D,
Stark Z,
Whiffin N,
Rehm H,
Ware J.
Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms. Genet Med. 2024;26(2):101029.
Keywords
JGM, Humans, Genetic Variation, Genetic Testing, Alleles, Databases, Genetic
JAX Source
Genet Med. 2024;26(2):101029.
ISSN
1530-0366
PMID
37982373
DOI
https://doi.org/10.1016/j.gim.2023.101029
Grant
P.N.R. was supported by the National Human Genome Research Institute grant U24HG011449.
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.
Comments
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).