High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

Abstract

Possession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

Ischemic Stroke and Pulmonary Arteriovenous Malformations

“…The most recent international guidelines for HHT management recommend that, when indicated, preventive antithrombotic regimens consist of either single antiplatelet or anticoagulant therapy, avoiding double antiplatelet therapy or combined antiplatelet and anticoagulant therapy. 24 These comments are expected to evolve in the near future as more evidence for individual variability in stroke risk (from concurrent genetic changes) 44 or pharmacogenomic variations in sensitivity/resistance to antiplatelets such as clopidogrel 45 emerge.…”

Functional filter for whole genome sequence data identifies stress impact, non-coding alternate polyadenylation site variants >5kb from coding DNA

“…All three patients with Variants 1 and 2 had clinically-confirmed HHT (10)(11)(12)(34)(35)(36)(37)(38)(39). The first-degree relatives with Variant 2 had no other identified cause to HHT.…”

“…The cohort recruited with HHT were particularly suited for GROFFFY methodological validation processes because a subset had not undergone prior genetic testing, and because clinical pipelines were incomplete at the time of GROFFFY analyses. This resulted in a validation dataset of 34 WGS sequences where clinical pipelines had identified a causal variant (35)(36)(37)(38)(39), and discovery dataset of 98 WGS sequences where some DNAs were expected to have heterozygous loss-of-function variants in ACVRL1, ENG or SMAD4 (10).…”

“…An autosomal dominant-specific disease application step was included as a high stringency "white list" filter. For this, the annotated WGS files were retrieved for the 34 Validation Set DNAs where a causative variant had already been identified in known HHT genes through clinical pipelines (35)(36)(37)(38)69). Variant information was collected through unique variant IDs consisting of chromosome number, variant starting position, reference sequence and altered sequence (e.g.…”