Clinical concordance evaluation of the causality of sequence variants

Abstract

Abstract Interpreting the sequence variants is a scientific challenge, as well as realistic task in clinical practice. The pathogenicity of variants depends not only on the 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-genetic feature of a patient with the pathogenic feature of candidate gene, including phenotype specificity, pathogenic genotype, genotype-phenotype (severity) correlation, and inheritance, which are associated with the GDQ. In 337 patients with epilepsy on genetic test, 70 variants were evaluated as pathogenic/likely pathogenic by American College of Medical Genetics and Genomics guideline (ACMG). The CCE identified all these pathogenic/likely pathogenic variants, but excluded the pathogenicity of one variant. The CCE identified additional 13 possible-causative, one likely-causative, and two causative variants, including a causative homozygous variant of MFSD8 associated with ceroid lipofuscinosis, which was evaluated to be uncertain significant by ACMG. The CCE is a framework with individualized criteria on the clinical phenotype of patient and the pathogenic features of individual gene, being potentially a practical protocol for individualized medicine of future.