Best practices for the interpretation and reporting of clinical whole genome sequencing

Abstract

Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.

Systematic evaluation of genome sequencing for the assessment of fetal structural anomalies

“…We computationally derived our candidate disease gene list to limit the burden of up-front gene curation and to account for the phenotypic heterogeneity of the fetal structural anomaly cohort. 26,48 We compiled a list of 2,535 genes from eight sources that are broadly associated with developmental disorders ( Table S3 ; Appendix ). SVs overlapping 64 known genomic disorder ( Table S4 ) or 17 pathogenic positional effect loci ( Table S5 ) were retained for further manual review.…”

“…of the fetal structural anomaly cohort. 26,48 We compiled a list of 2,535 genes from eight sources that are broadly associated with developmental disorders (Table S3; Appendix). SVs overlapping 64 known genomic disorder (Table S4) or 17 pathogenic positional effect loci (Table S5) were retained for further manual review.…”

“…The GS analytic framework developed in this study also maintained a manageable variant review burden, which can present significant barriers to the widespread implementation of clinical GS. 25,26 We conclude by highlighting the approaches used to interpret variants uniquely identified by GS, which will be broadly applicable to a wide variety of indications for testing.…”

Targeting de novo loss of function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

“…5 Adding this additional review approach, along with a phenotype-driven variant analysis, is consistent with recently released best practices in genome analysis released from the Medical Genome Initiative. 26 From reviewing 20 genomes, we estimate this approach would yield 3-9 potential additional variants per trio, using a LOEUF cut off <0.35, a missense constraint z-score >3, 27 and likely pathogenic/pathogenic ClinVar entries with 2 stars or above. Our hope is to achieve a higher diagnostic yield per number of variants assessed by diagnostic labs, whereby we prioritise the most salient variants first.…”

Editorial: Improving medical diagnosis in rare diseases

“…The diagnostic yields of NGS in RDs varies (24–68%) depending on the technology employed, the disease group studied, the patient age groups, clinical indications, family structures and variant types analysed ( Clark et al, 2018 ). Genome test interpretation and reporting represents one of the challenges to laboratories seeking to implement or maximize the diagnostic yield of NGS, and guidelines have just been published in order to address this gap ( Austin-Tse et al, 2022 ). Even though NGS affords us a better opportunity to elucidate the genetic causes of RDs, a proportion of individuals remain undiagnosed.…”