Genome Alert!: a standardized procedure for genomic variant reinterpretation and automated genotype-phenotype reassessment in clinical routine

Abstract

Numerous countries have set up population genomics plans, allowing an unprecedented growth in the ability of interpreting variants in human diseases. Retrospective interpretation of sequenced data in the light of the current literature is a major concern of the field. Moreover, such reinterpretation is manual and both the human resources and the variable operating procedures are main bottlenecks. This work describes the Genome Alert! standardized procedure. This open-source method automatically reports changes with potential clinical significance in variant classification between releases of the ClinVar database. Using ClinVar submissions across time, this method assigns gene-disease associations validity category. Genome Alert! was assessed on a retrospective 29 months multicentric series of 5,959 consecutive individuals screened by targeted or exome sequencing. Between July 2017 and December 2019, the retrospective analysis of ClinVar submissions revealed a monthly median of 1,247 changes in variant classification with potential clinical significance and 23 new gene-disease associations. Reexamination of 4,929 targeted sequencing files highlighted 45 changes, which 89% classifications were expert validated, leading to four additional diagnoses. Genome Alert! gene-disease association catalog provided 75 high-confidence associations not available in the OMIM morbid list, where 20% became OMIM morbid 8 months later. Over 356 negative exome sequencing data that were reannotated for variants in these 75 genes, this elective approach led to a new diagnosis. Genome Alert! (https://genomealert.univ-grenoble-alpes.fr/) enables the systematic and reproducible reinterpretation of acquired sequencing data in a clinical routine with a limited human resource impact. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/21260422v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@1d5247eorg.highwire.dtl.DTLVardef@4ee1a6org.highwire.dtl.DTLVardef@c08ecaorg.highwire.dtl.DTLVardef@1de7964_HPS_FORMAT_FIGEXP M_FIG C_FIG