Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation

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 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.