[MS5-3A-4] Phenotype-Driven Designing “Virtual Panels” is Efficiency for Analyzing the Date of Case-Only Clinical-Whole-Exome Sequencing
Background: Whole-exome sequencing (WES) presents a promising method for diagnosing patients with a complex phenotype, which has largely contributed to the identification of new disease-causing genes and is now entering clinical laboratories. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. How to analyze、interpret and filter thousands of detected variants and pick up the variant(s) relative to patient phenotype from numerous variants can be challenging in some scenarios, particularly clinical assessment of rare complex phenotypes and refractory clinical cases, for physicians. Given of these bothersome handicap，we expect to an efficiency、easy and practical case-only Clinical-whole-exome sequencing date analyzing workflow.
Results: We develop an efficiency、easy and practical case-only clinical-whole-exome sequencing date analyzing workflow, which is utilized to computational phenotype-derived analysis software. We retrospectively analyzed the complex phenotypes of a proband who are near the end of the diagnostic odyssey. The core phenotypes of the proband are including hypotonia、seizures、global developmental delay、cerebral atrophy. We designed the “Virtual candidate genes panel” by the computational phenotype-derived analysis software. Then, we re-analyzed the case-only-WES date by the workflow. We selected two candidate variants c.430T>C、c.640G>C on PMM2 gene. The candidate causal variatins were confirmed by means of Sanger sequencing, and consistent with co-segregation analyzes among the family.
Conclusions: The strategies we present may improve efficiency and potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using whole sequencing techniques. we propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. we expect our integrative paradigm can build the bridge between clinicians and WES date.
Results: We develop an efficiency、easy and practical case-only clinical-whole-exome sequencing date analyzing workflow, which is utilized to computational phenotype-derived analysis software. We retrospectively analyzed the complex phenotypes of a proband who are near the end of the diagnostic odyssey. The core phenotypes of the proband are including hypotonia、seizures、global developmental delay、cerebral atrophy. We designed the “Virtual candidate genes panel” by the computational phenotype-derived analysis software. Then, we re-analyzed the case-only-WES date by the workflow. We selected two candidate variants c.430T>C、c.640G>C on PMM2 gene. The candidate causal variatins were confirmed by means of Sanger sequencing, and consistent with co-segregation analyzes among the family.
Conclusions: The strategies we present may improve efficiency and potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using whole sequencing techniques. we propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. we expect our integrative paradigm can build the bridge between clinicians and WES date.