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Clinical validity of expanded carrier screening: Evaluating the gene‐disease relationship in more than 200 conditions
Author(s) -
Balzotti Marie,
Meng Linyan,
Muzzey Dale,
Johansen Taber Katherine,
Beauchamp Kyle,
Curation Team Myriad Genetics,
Curation Team Baylor Genetics,
MarHeyming Rebecca,
Buckley Bethany,
Moyer Krista
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24033
Subject(s) - concordance , disease , guideline , biology , gene , genetic association , computational biology , genetics , bioinformatics , medicine , genotype , pathology , single nucleotide polymorphism
Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene‐disease association to assess the clinical validity of conditions screened by ECS panels. The Clinical Genome Resource (ClinGen) gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty‐one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions. All 208 evaluated conditions met the evidence threshold for supporting a gene‐disease association. Furthermore, 203 of 208 (98%) achieved the strongest (“Definitive”) level of gene‐disease association. All conditions evaluated by both commercial laboratories were similarly classified. Assessment using the ClinGen standardized framework revealed strong evidence of gene‐disease association for conditions on two ECS panels. This result establishes the disease‐level clinical validity of the panels considered herein.