PTC clinical correlations in HHT cohorts. (A) Cohort 1 population first described by Joyce et al.³⁷ (i) Molecular subtypes in the 3 endothelial-expressed HHT genes. Note splice variants and multiexon deletions do not enable PTC-generating consequences to be predicted³⁸ and were not examined further. (ii/iii) HHT phenotypes in patients with (ii) ACVRL1^+/− and (iii) ENG^+/− according to PTC ∗(red) and non-PTC (blue) categories, with exact molecular subtype, color scheme as indicated. Note that throughout the figures, for consistency, ACVRL1^+/− is pink/purple; ENG^+/− is blue, and SMAD4^+/− is orange. P values calculated by Mann-Whitney U test. (B) Cohort 2 population, first described with bleeding scores by Shovlin et al² (see also supplemental Methods). (i) Molecular subtypes annotated as in panel Ai. (ii/iii) Histograms of bleeding scores with superimposed normal and Kernal cosine distributions, for patients with heterozygous (ii) ACVRL1 and (iii) ENG causal variants. PTC/non-PTC P values calculated by Mann-Whitney U test. (C) Cohort 3: newly described nosebleed ointment cohort (further details provided in supplemental Figure 1). (i) Flowchart of treatment numbers 09/04/1999 to 17/03/2005; patients reporting a response; and patients genotyped. (ii) All 41 reported responses by qualitative description and applied grade. (iii) All 22 reported responses in patients with a causal HHT gene variant identified, by variant type and causal gene (pink, ACVRL1; blue, ENG; and orange, SMAD4). Splice variants are shown separately because RNA consequences are unclear³⁸ and differed when tested in different members of the same family (C. L. Shovlin, unpublished data, 2012). Pairwise P value calculated by Dunn's test after Kruskal-Wallis test. AVM, arteriovenous malformation; NB, nosebleed.