2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Development of a Comprehensive Cardiovascular Disease Whole Genome Sequencing Test

Pdf Summary

Illumina, Inc. has developed a comprehensive cardiovascular disease (CVD) whole-genome sequencing (WGS) test. The test focuses on CVD indications with a high likelihood of a genetic cause and relevance in an adult cardiac clinic population, such as aortopathy, arrhythmia, cardiomyopathy, dyslipidemia, hypertension, and thrombophilia. The associated genes for the panel were identified through a literature review and assessment of commercially available panels.<br /><br />The test sensitivity for the CVD panel genes was evaluated by assessing the confidence in calling variants with a pathogenic or likely pathogenic classification. Variants likely to impact the protein sequence and with a minor allele frequency (MAF) below 5% were classified as pathogenic or likely pathogenic.<br /><br />To estimate the burden of variant triage per case, negative and positive WGS cases were tested. The WGS data was generated using Illumina's TruSeq PCR-free kit, and variants were called using the DRAGEN version 3.8.4 pipeline.<br /><br />The development of the CVD gene panel involved curating gene-disease relationships (GDRs). Existing GDRs with definitive or strong classifications were included, and additional gene-disease pairs were curated using the ClinGen framework. The final panel included 205 gene-disease pairs.<br /><br />The evaluation of WGS performance showed successful calling of 99.4% of ClinVar pathogenic or likely pathogenic single nucleotide variants in the CVD panel genes.<br /><br />The bioinformatics approach included evaluating over 7.4 million variants in the gnomAD database and classifying them as benign or likely benign. The mean number of variants requiring triage per case across 53 WGS cases was 2.5.<br /><br />Overall, the development of the CVD WGS test highlights the investment in clinical and bioinformatic resources required for a robust molecular test. The use of WGS for CVD testing may improve access to relevant genetic risk information. Ongoing curation and bioinformatics support are necessary for the implementation of clinical tests based on WGS.

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Presenting Author - Laura Amendola, MS, CGC; Co-Author - Alison J. Coffey, PhD; Co-Author - Samuel P. Strom, PhD; Co-Author - Akanchha Kesari; Co-Author - James Avecilla, BS; Co-Author - Josh Lowry, PhD; Co-Author - Stetson Thacker, PhD; Co-Author - Julie Taylor, PhD; Co-Author - Kathryn Golden-Grant, MS, CGC; Co-Author - Matt Brown, PhD; Co-Author - Becky Milewski, MS; Co-Author - John Belmont, MD; Co-Author - Denise L. Perry, MS; Co-Author - Ryan J. Taft, PhD;

Meta Tag

Cardiac/circulatory disorders

Cardiovascular System

Genetic Testing

Genome sequencing

Co-Author Alison J. Coffey, PhD

Co-Author Samuel P. Strom, PhD

Co-Author Akanchha Kesari

Co-Author James Avecilla, BS

Co-Author Josh Lowry, PhD

Co-Author Stetson Thacker, PhD

Co-Author Julie Taylor, PhD

Co-Author Kathryn Golden-Grant, MS, CGC

Co-Author Matt Brown, PhD

Co-Author Becky Milewski, MS

Co-Author John Belmont, MD

Co-Author Denise L. Perry, MS

Co-Author Ryan J. Taft, PhD

Presenting Author Laura Amendola, MS, CGC

Keywords

Illumina, Inc.

cardiovascular disease

whole-genome sequencing

CVD indications

gene panel

pathogenic variants

variant triage

bioinformatics approach

gnomAD database

genetic risk information