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 in which loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 patients with HHT from a single reference center recruited to the 100 000 Genomes Project were categorized on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data were tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, or 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. Deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff scores. CADD >15 variants were identified in 38/104 (36.5%) patients with HHT, 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 = .008) and coagulation (Spearman ρ = 0.21; P = .024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann-Whitney test P = .021). In conclusion, patients with HHT commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalized medicine strategies.

DNA variant classification-reconsidering "allele rarity" and "phenotype" criteria in ACMG/AMP guidelines.

Recent guidance suggested modified DNA variant pathogenicity assignments based on genome-wide allele rarity. Different a priori probabilities of pathogenicity operate where patients already have clinical diagnoses, and are found to have a very rare variant in a gene known to cause their disease, compared to predictive testing of a clinically unaffected individual. We tested new recommendations from the ClinGen Sequence Variant Interpretation Working Group for ClinVar-listed, loss-of-function variants meeting the very strong evidence of pathogenicity criterion [PVS1] in genes for 3 specific diseases where causal gene identification can modify clinical care of an individual- Von Willebrand disease, cystic fibrosis and hereditary haemorrhagic telangiectasia. Across these diseases, current rules leave 20/1,278 (1.6%) of loss-of-function variants as variants of uncertain significance (VUS that may not be reported to clinicians), and 207/1,278 (17.2%) as likely pathogenic. Applying the new ClinGen rule enabling PVS1 and the allele rarity criterion PM2 to delineate likely pathogenicity still left 8/1,278 (0.9%) as VUS (reflecting non-PVS1 calls by the submitters), and the majority of null alleles meeting PVS1 as merely likely pathogenic. We favour an approach whereby, for PVS1 variants in patients who personally meet the phenotypic PP4 criterion for a disease where casual variants are commonly family-specific, that PM2 is upgraded to permit a pathogenic call. Of 1,278 ClinVar-listed frameshift, nonsense and canonical splice site variants that met PVS1 in the 3 conditions, 16.0% (204/1,278) would be newly designated as pathogenic, avoiding misinterpretation outside of clinical genetics communities. We suggest further discussion around variant assessment across different clinical applications, potentially guided by PP4 alerts to distinguish personal versus family phenotypic history.