The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT-causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 HHT patients from a single reference centre recruited to the 100,000 Genomes Project were categorised on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, hemoglobin, erythrocyte enzyme and erythrocyte membrane constituents. Rare variants (all GnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes, and in 38/104 (36.5%) of the HHT patients. Likely deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff (MSC) scores. CADD>15 variants were found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann Whitney p=0.021). In conclusion, HHT patients commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalised medicine strategies.
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.
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