The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care

Shovlin, CL; Buscarini, Elisabetta; Sabbá, Carlo; Mager, Hans Jurgen; Kjeldsen, Anette Drøhse; Pagella, Fabio; Sure, Ulrich; Ugolini, Sara; Toerring, Pernille Mathiesen; Suppressa, Patrizia; Rennie, Catherine; Post, Martijn C.; Patel, Maneesh C.; Nielsen, Troels Halfeld; Manfredi, Guido; Lefroy, David; Kariholu, Ujwal; Jones, B.; Fialla, Annette Dam; Dupuis, Olivier; Droege, Freya; Coote, Nicky; Boccardi, Edoardo; Alsafi, Ali; Alicante, Saverio; Dupuis‐Girod, Sophie

doi:10.1016/j.ejmg.2021.104370

Cited by 34 publications

(56 citation statements)

References 36 publications

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“…Of note, the c.1282T>C variant in this family has the highest CADD pathogenicity score, whereas some variants now appear likely benign on the basis of low pathogenicity scores, and population frequencies greater than 1/10,000 (Table S1). Nevertheless, they both had three Curaçao Criteria, unlike other ACVRL1 +/À and ENG +/À confirmed HHT cases in our cohort (Sharma et al, 2021), and were not "atypical" as seen by us for patients with EPHB4 +/À and other vasculopathies (Shovlin et al, 2021). WGS identified the scale of genetic variation between the family members, and studies to identify variants potentially relevant to the pulmonary AVM and cirrhotic phenotypes are ongoing.…”

Section: Discussionsupporting

confidence: 62%

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

Balachandar

Graves

Shimonty

et al. 2021

American J of Med Genetics Pt A

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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this

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Section: Discussionsupporting

confidence: 62%

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

Balachandar

Graves

Shimonty

et al. 2021

American J of Med Genetics Pt A

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“…Next, we focussed on iron treatment which is an injurious stimulus particularly relevant to HHT patients, 5–9 that we had also previously examined using RNASeq in normal endothelial cells (HDMECs), demonstrating upregulation of multiple mRNAs within 1 hour. 33 We tested if iron-induced differential alignments in normal primary HDMECs differed according to whether the gene was in the HHT list (Figure 6E), ND list (Figure 6Fi) or a random gene list (Figure 6Fi), and demonstrated that the ND list genes displayed higher alignments in HDMEC following 1hr treatment with 10μM iron (Figure 6Ei).…”

Section: Resultsmentioning

confidence: 99%

“…57, 58 Furthermore, experimental studies link ENG , ACVRL1 and SMAD4 deficiency to reductions in endothelial integrity, 21, 23, 24 relevant to the core clinical HHT phenotype of hemorrhage. 5–9 Amongst the top 50 HHT-differentially aligned genes, many encode extracellular proteins that regulate TGF-β/BMP signalling including periostin 56 ( POSTN) , fibulin-6/hemicentin 1 59, 60 ( HMCN1) , lysyl oxidase-like 2 61 ( LOXL2 ), SPARC-related modular calcium binding protein 2 62 ( SMOC2) , laminin receptor 1 ( RSPA ), 63 and fibrillin 1 ( FBN1 , Figure 4F, Supplementary Figure 7) 58 Likely relevance was further enhanced because BMP/TGF-β ligand release from extracellular pools is by matrix metallopeptidases, 64, 65 a further GO term enriched in the HHT BOEC datasets (through 8 genes, most significantly ADAMTS18 , and MMP24 , Figure 4F, Supplementary Figure 7). Our initial expectation was that their modulation may be further cellular adaptive responses that enable more ACVRL1 +/- , ENG +/- and SMAD4 +/- BOECs to survive, analogous to lower ALK5 and ALK1 receptor expression/signalling.…”

Section: Discussionmentioning

confidence: 99%

“…We focussed on patients with the vascular dysplasia hereditary hemorrhagic telangiectasia (HHT) where new treatments are required to further reduce morbidity from hemorrhage caused by abnormal blood vessels. 5–14 HHT is inherited as an autosomal dominant trait, and typically caused by heterozygous, loss-of-function variants in ACVRL1, ENG and SMAD4 . 15–17 As recently reviewed, 16, 17 these genes encode endothelial-cell expressed proteins that transmit or modify signalling by the BMP/TGF-β superfamily, with HHT causality confirmed by null, heterozygous and endothelial-specific disease gene models.…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous transcriptional signatures unmask variable premature termination codon (PTC) burden alongside pathway-specific adaptations in blood outgrowth endothelial cells from patients with nonsense DNA variants causing hereditary hemorrhagic telangiectasia

Bernabeu-Herrero

Patel

Bielowka

et al. 2021

Preprint

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In order to identify cellular phenotypes resulting from nonsense (gain of stop/premature termination codon) variants, we devised a framework of analytic methods that minimised confounder contributions, and applied to blood outgrowth endothelial cells (BOECs) derived from controls and patients with heterozygous nonsense variants in ACVRL1, ENG or SMAD4 causing hereditary haemorrhagic telangiectasia (HHT). Following validation of 48 pre-selected genes by single cell qRT-PCR, discovery RNASeq ranked HHT-differential alignments of 16,807 Ensembl transcripts. Consistent gene ontology (GO) processes enriched compared to randomly-selected gene lists included bone morphogenetic protein, transforming growth factor-β and angiogenesis GO processes already implicated in HHT, further validating methodologies. Additional terms/genes including for endoplasmic reticulum stress could be attributed to a generic process of inefficient nonsense mediated decay (NMD). NMD efficiency ranged from 78-92% (mean 87%) in different BOEC cultures, with misprocessed mutant protein production confirmed by pulse chase experiments. Genes in HHT-specific and generic nonsense decay (ND) lists displayed differing expression profiles in normal endothelial cells exposed to an additional stress of exogenous 10μmol/L iron which acutely upregulates multiple mRNAs: Despite differing donors and endothelial cell types, >50% of iron-induced variability could be explained by the magnitude of transcript downregulation in HHT BOECs with less efficient NMD. The Genotype Tissue Expression (GTEx) Project indicated ND list genes were usually most highly expressed in non-endothelial tissues. However, across 5 major tissues, although 18/486 nonsense and frameshift variants in highly expressed genes were captured in GTEx, none were sufficiently prevalent to obtain genome-wide significant p values for expression quantitative trait loci (GnomAD allele frequencies <0.0005). In conclusion, RNASeq analytics of rare genotype-selected, patient-derived endothelial cells facilitated identification of natural disease-specific and more generic transcriptional signatures. Future studies should evaluate wider relevance and whether injury from external agents is augmented in cells with already high burdens of defective protein production.

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“…In 2016, six countries set up a working group dedicated to HHT within what becam the European Reference Network on Rare Multisystemic Vascular Diseases [18]. The patient was treated with a proton pomp inhibitor infusion and iron infusion.…”

Section: Discussionmentioning

confidence: 99%

A Rare Case of Upper Gastrointestinal Bleeding: Osler-Weber-Rendu Syndrome

Jargielo

Rycyk

Kasztelan-Szczerbińska

et al. 2022

Medicina

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Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia (HHT), is a rare, autosomal dominant condition that affects approximately 1 in 5000 patients causing abnormal blood vessel formation. HHT patients have mucocutaneous telangiectasias and arteriovenous malformations in various organs. The most prominent symptom of HHT is epistaxis, which, together with gastrointestinal bleeding, may cause iron deficiency anemia. This study is a case report of a 62-year-old patient who was admitted to the Department of Gastroenterology due to acute upper gastrointestinal bleeding and a history of recurrent epistaxis and melena for 4 days, which was confirmed in digital rectal examination. Urgent upper gastrointestinal endoscopy revealed active bleeding from multiple angioectatic spots with bright-looking salmon-colored patches in the antrum and the body suggestive of HHT. The bleeding from two angioectatic spots was stopped by argon plasma coagulation, and four clips were placed to provide good hemostasis. The patient was treated with a proton pomp inhibitor infusion and iron infusion. She was discharged with no signs of GI bleeding, normalized iron levels and a diagnosis of HHT. She was referred to further genetic testing, including evaluation of first-degree relatives. She also had performed unenhanced thin-cut computed tomography (CT) with angiography to exclude the presence of pulmonary arteriovenous malformations (PAVMs). Due to the fact that the patient did not manifest any other HHT-related symptoms and that the instrumental screening discloses no silent AVMs in other organs, the “watch-and-wait strategy” was applied. Although, Osler-Weber-Rendu syndrome is widely described in the medical literature, effective treatment of gastrointestinal telangiectasias is not always available and still lacks standardization to date, which makes the management of gastroenterological involvement still a challenging issue.

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The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care

Cited by 34 publications

References 36 publications

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

Heterozygous transcriptional signatures unmask variable premature termination codon (PTC) burden alongside pathway-specific adaptations in blood outgrowth endothelial cells from patients with nonsense DNA variants causing hereditary hemorrhagic telangiectasia

A Rare Case of Upper Gastrointestinal Bleeding: Osler-Weber-Rendu Syndrome

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