Clinical concordance evaluation of the causality of sequence variants

Abstract Interpreting sequence variants is a scientific challenge as well as a realistic task in clinical practice. The pathogenicity of a variant depends on not only its damage but also the genetic dependent quantity (GDQ, quantitative genetic function required for normal life) that differs in each gene but was not considered in previous protocols. We developed a clinical concordance evaluation (CCE) framework to evaluate the pathogenicity/causality of variants by comparing the clinical and genetic features of a patient with the pathogenic features of candidate genes, including phenotype specificity, pathogenic genotype, genotype-phenotype (severity) correlation, and inheritance, which are associated with GDQ. In 337 patients with epilepsy on genetic testing, 70 variants were evaluated as pathogenic/likely pathogenic by the American College of Medical Genetics and Genomics guidelines (ACMG). The CCE identified all these pathogenic/likely pathogenic variants but excluded the pathogenicity of one variant. The CCE identified an additional 13 possibly-causative, one likely-causative, and two causative variants, including a causative homozygous variant of MFSD8 associated with ceroid lipofuscinosis, which was evaluated as “uncertain significance” by ACMG. CCE is a framework with individualized criteria for the clinical/genetic abnormalities of patients and the pathogenic features of individual genes, potentially a practical protocol for individualized medicine.