Genomize-SEQ: an NGS data analysis platform for genomic variant classification and prioritization

Abstract Accurate interpretation of diverse genetic variants remains a pivotal challenge in the diagnosis of rare diseases. Although evidence-based guidelines established by the American College of Medical Genetics and Genomics have enhanced the precision of variant assessment, the practical implementation of this evidence-based classification can be challenging. The inherent genetic heterogeneity in rare diseases, coupled with the need to integrate information from numerous databases, contributes to this complexity. Therefore, advancements in secondary variant calling, automated variant annotation and prioritization, visualization of variant annotations with the raw data, and a streamlined reporting process are crucial for efficient and robust analysis. Here we present Genomize-SEQ, a web-based clinical genomics analysis software that has all of these capabilities, with which more than 300,000 patients have been analyzed to date. Genomize-SEQ collects data from more than 120 different databases to annotate the variants according to ACMG/AMP guidelines and prioritize the variants that could be causative for the clinical presentation of a patient. Genomize-SEQ can also perform real-time data aggregation to calculate variant frequencies in each center as well as the community. This capability helps clinicians to analyze variants more easily in regions without genome projects or in populations underrepresented in existing databases. We validated the annotation capacity of Genomize-SEQ by performing a systematic comparison of ACMG pathogenicity prediction from widely used algorithms and Genomize-SEQ’s algorithm, using ClinGen’s expert curation dataset as a truth set. In addition, we tested the prioritization efficiency of Genomize-SEQ by using real-world whole-exome sequencing data of 215 patients with pre-diagnostic and phenotypic information. Genomize-SEQ identified the causative variants with a 97% success rate, with 52% of these variants ranked in the top position and over 90% ranked within the top 20. Thus, Genomize-SEQ provides a complete solution for comprehensive variant interpretation to achieve fast and reliable diagnosis for rare diseases from next-generation sequencing data.