Abstract:Hereditary haemorrhagic telangiectasia (HHT) can result in challenging anaemia and thrombosis phenotypes. Clinical presentations of HHT vary for relatives with identical casual mutations, suggesting other factors may modify severity. To examine objectively, we developed unsupervised machine learning algorithms to test whether haematological data at presentation could be categorised into sub‐groupings and fitted to known biological factors. With ethical approval, we examined 10 complete blood count (CBC) variab… Show more
“…All three individuals with variants 1 and 2 had clinically confirmed HHT. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 35 , 66 After identification of the SMAD4 variants, recruiting clinicians also reported SMAD4- compatible clinical phenotypes: The first-degree relatives with variant 2 had no other identified cause to HHT. They each experienced daily nosebleeds and had classical HHT telangiectasia, and one had pulmonary arteriovenous malformations requiring treatment and hemihypertrophy (left-right axis defect).…”
Section: Resultsmentioning
confidence: 99%
“…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. 13 , 14 , 15 , 16 , 34 , 35 Variant information was collected through unique variant IDs consisting of chromosome number, variant starting position, reference sequence, and altered sequence (e.g., chr1:111_C/TTT). To confirm that no two variants were represented by the same variant ID, the full list was compared to a set where only unique values were stored, and the two lists were identical.…”
“…All three individuals with variants 1 and 2 had clinically confirmed HHT. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 35 , 66 After identification of the SMAD4 variants, recruiting clinicians also reported SMAD4- compatible clinical phenotypes: The first-degree relatives with variant 2 had no other identified cause to HHT. They each experienced daily nosebleeds and had classical HHT telangiectasia, and one had pulmonary arteriovenous malformations requiring treatment and hemihypertrophy (left-right axis defect).…”
Section: Resultsmentioning
confidence: 99%
“…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. 13 , 14 , 15 , 16 , 34 , 35 Variant information was collected through unique variant IDs consisting of chromosome number, variant starting position, reference sequence, and altered sequence (e.g., chr1:111_C/TTT). To confirm that no two variants were represented by the same variant ID, the full list was compared to a set where only unique values were stored, and the two lists were identical.…”
“…Case notes were reviewed with ethical approval from the Hammersmith and Queen Charlotte’s and Chelsea Research Ethics Committee (LREC 2000/5764). Key findings in this cohort referring to individual clinical features corresponding to the respective genetic variants were published previously [ 57 , 71 , 72 , 85 ]. In the current study, we focused on the variants and the number of times each variant was reported.…”
Section: Methodsmentioning
confidence: 99%
“…Large prospectively-accrued series have identified environmental factors that contribute to more severe clinical manifestations once AVMs are present, particularly anaemia aggravating high-output states [ 49 ] and associated with earlier mortality [ 50 , 51 ]. Additionally, we have identified that in HHT, iron deficiency is associated with venous thromboemboli [ 52 ] and ischaemic strokes through pulmonary AVMs [ 53 ]; iron treatments can be associated with worsening nosebleeds in approximately 1 in 20 patients [ 54 , 55 ]; higher serum iron levels and intravenous iron treatments are independent risk factors for cerebral abscess due to pulmonary AVMs [ 56 ]; and, most recently, that unsupervised machine learning identifies relevant heterogeneity in blood indices [ 57 ]. Despite HHT clinical risks, recent European studies have shown that life expectancy is normal, or near-normal, in HHT [ 50 , 58 , 59 , 60 ].…”
Section: Introductionmentioning
confidence: 99%
“…factors for cerebral abscess due to pulmonary AVMs [56]; and, most recently, that unsupervised machine learning identifies relevant heterogeneity in blood indices [57]. Despite HHT clinical risks, recent European studies have shown that life expectancy is normal, or near-normal, in HHT [50,[58][59][60].…”
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in ACVRL1 (encoding activin receptor-like kinase 1 [ALK1]), ENG (encoding endoglin [CD105]), or SMAD4. In a consecutive single-centre series of 37 positive clinical genetic tests performed in 2021–2023, a skewed distribution pattern was noted, with 30 of 32 variants reported only once, but ACVRL1 c.1231C>T (p.Arg411Trp) identified as the disease-causal gene in five different HHT families. In the same centre’s non-overlapping 1992–2020 series where 110/134 (82.1%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was identified in nine further families. In a 14-country, four-continent HHT Mutation Database where 181/250 (72.4%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was reported by 12 different laboratories, the adjacent ACVRL1 c.1232G>A (p.Arg411Gln) by 14, and ACVRL1 c.1120C>T (p.Arg374Trp) by 18. Unlike the majority of HHT-causal ACVRL1 variants, these encode ALK1 protein that reaches the endothelial cell surface but fails to signal. Six variants of this type were present in the three series and were reported 6.8–25.5 (mean 8.9) times more frequently than the other ACVRL1 missense variants (all p-values < 0.0039). Noting lower rates of myocardial infarction reported in HHT, we explore potential mechanisms, including a selective paradigm relevant to ALK1′s role in the initiating event of atherosclerosis, where a plausible dominant negative effect of these specific variants can be proposed. In conclusion, there is an ~9-fold excess of kinase-inactive, cell surface-expressed ACVRL1/ALK1 pathogenic missense variants in HHT. The findings support further examination of differential clinical and cellular phenotypes by HHT causal gene molecular subtypes.
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