Clinical concordance evaluation of the causality of sequence variants

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.

Gene-disease association: pathogenic potential/pathogenic feature assessment

“…The pathogenic feature includes what kind of phenotype a gene is associated with (speci c phenotype), the inheritance pattern, and the genotype-phenotype correlation, such as a distinct pathogenic genotype for a phenotype, genotype-severity correlation, and submolecular implication of the variants. In addition to the pathogenic potential, the PPA evaluates the gene-disease associations with information on how a gene is associated with a disease, which re ects the gene-disease association and provides the bases for evaluating the pathogenicity/causality of the genetic variants 25 , being critical for the clinical diagnosis of genetic diseases.…”

“…Therefore, if a gene was associated with a spectrum of phenotypes that were correlated with genotypes, a point could be obtained. Phenotype speci city is the rst consideration in evaluating the pathogenicity of variants in a gene 25 and is critical for the clinical diagnosis of genetic diseases.…”

“…More importantly, in addition to the scoring and pathogenicity classi cation, the PPA evaluates and presents how a gene is associated with the phenotype (the pathogenic feature), including speci c phenotype, pathogenic genotype and mechanisms, genotype-phenotype correlation with submolecular implication of the variants, and inheritance pattern. This information is required for individualized evaluation of the pathogenicity/causality of variants 25 and clinical diagnosis of genetic diseases. Among the 19,711 functioning genes in human beings 12 , 3,623 genes have now been evaluated to be "pathogenic" or "possibly pathogenic", whereas the pathogenic potential in most (16,088 genes) remains to be con rmed or unknown.…”

“…LOF of KCND3 was associated with spinocerebellar ataxia 40 , whereas GOF of KCND3 was associated with Brugada syndrome 41 . In addition to the consequences of variants ( c), PPA advocates the determination of correlation between functional impairment and phenotype by functional studies, including funotype-phenotype correlation and quantitative correlation between functional impairment and phenotype severity ( d), which are useful for clinical diagnosis of genetic diseases 25 .…”

“…The PPA evaluated the pathogenic feature of each gene with the details of evidence summarized and presented in the GD&P database (https://www.gdap.org.cn/). The information included the clinical characteristics of the geneassociated phenotype (speci c phenotype), the pathogenic genotype and mechanisms, the genotype-phenotype correlation with submolecular and other implications of the variants on phenotype severity, and the inheritance pattern, which are critical for the clinical diagnosis of genetic diseases and are the bases for evaluating the pathogenicity/causality of genetic variants 25 .…”