ENG Genes Research Articles

Arteriovenous Malformations in Osler-Weber-Rendu Syndrome: Pathophysiology, Clinical Manifestations, and Advances in Management

Osler-Weber-Rendu Syndrome, or Hereditary Hemorrhagic Telangiectasia (HHT), is a rare genetic disorder marked by the development of arteriovenous malformations (AVMs) throughout the body. These abnormal vascular connections bypass the capillary network, leading to significant clinical challenges. This article reviews the pathophysiology, clinical manifestations, and advances in the management of AVMs in HHT. The genetic basis of HHT involves mutations in the ENG, ACVRL1, and SMAD4 genes, which play critical roles in the TGF-β signaling pathway. These mutations result in endothelial dysfunction, contributing to the formation of AVMs. The clinical impact of AVMs is significant, particularly when they occur in the brain, lungs, liver, or gastrointestinal tract, where they can lead to life-threatening complications. This review also explores current diagnostic and management strategies, emphasizing the importance of a multidisciplinary approach. Interventional techniques such as embolization, stereotactic radiosurgery, and microsurgical resection are discussed, alongside emerging therapies like anti-angiogenic drugs and gene therapy. These advancements have led to more personalized and effective treatment plans for patients. As a result, the management of AVMs in HHT has seen significant progress, with a growing emphasis on individualized care. Continued research and the development of specialized treatment centers are crucial for further improving patient outcomes in this complex condition.

Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes—ENG and ACVRL1

The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.

Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT.Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH).In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients.This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

Senkyunolide B exhibits broad-spectrum antifungal activity against plant and human pathogenic fungi via inhibiting spore germination and destroying the mature biofilm.

Aspergillus infection seriously jeopardize the health and safety of life of immunocompromised patients. The emergences of antifungal resistance highlight a demand to find new effective antifungal drugs. Angelica sinensis is a medicine-food herb and phthalides are its characteristic components. A few of phthalides have been reported to display satisfactory antifungal activities against plant pathogenic fungi. However, the structure activity relationships and antifungal action mechanism of phthalides remain to be further explored and elucidated. The antifungal activities of five natural phthalides and four artificial analogues were investigated, and their structure activity relationships were preliminarily elucidated in current study. The benzene ring moiety played an essential role in their antifungal activities; the oxygen-containing substituents on the benzene ring obviously impact their activities, the free hydroxyl was favorable to the activity. Typical phthalide senkyunolide B (SENB) exhibited broad antifungal activities against human and plant pathogenic fungi, especially, Aspergillus fumigatus. SENB affected the spore germination and hyphae growth of A. fumigatus via downregulating phosphatidylinositol-PKC-calcineurin axis and the expression of ENG genes. Moreover, SENB disturbed the oxidation-reduction process in A. fumigatus to destroy the mature biofilms. In vivo experiments indicated SENB significantly prolonged survival and decreased fungal burden in mouse model of invasive pulmonary aspergillosis. Phthalides could be considered as the valuable leads for the development of antifungal drug to cure plant and human disease. This article is protected by copyright. All rights reserved.

First genetic characteristics of Polish patients with idiopathic pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a rare, severe disorder of multifactorial origin. Genetic alterations in BMP/SMAD pathways were previously associated with disease development, however the exact role of other genetic factors from BMP/SMAD signalling is still unclear. Purpose We aimed to search for known PAH-associated mutations and potential novel variants responsible for disease onset in Polish PAH patients. Methods We prospectively recruited 93 consecutive idiopathic PAH patients from a single pulmonary hypertension reference centre between years 2009 and 2020. Eligible patients had pre-capillary pulmonary hypertension with pulmonary vascular resistance >3 Wood units in the absence of other causes of pre-capillary pulmonary hypertension. The presence of large gene rearrangements was analyzed by the Multiplex Ligation-dependent Probe Amplification (MLPA) reactions in the ENG, ACVRL1 and BMPR2 genes (SALSA MLPA Kit, MRC-Holland). We have further sequenced a panel of selected 48 genes from BMP/SMAD and related pathways using next-generation sequencing (SureSelect XT library preparation Kit, Agilent; NextSeq 500 sequencer, Illumina) and assessed causative potential of rare variants (minor allele frequency in non-finish Europeans below 1%) with Mutation Taster web-based tool. Results We identified at least one likely-causative variant of investigated genes in 51 (54.8%) subjects. Large genomic rearrangements were found by MLPA in 2 patients in ENG and ACVRL1 (ALK1) genes. We have found mutations in BMPR2 gene in 12 patients (12.5%) from our cohort with most variants present in one sample and 3 variants present in 2 samples. Mutations were located mostly in protein kinase domain (6 variants) and Activin type I and II receptor domain (2 variants). We have found 5 likely pathogenic variants in 6 patients in genes previously associated with PAH other than BMPR2 (SMAD9, KCNA5, KCNK3, EIF2AK4). In total, potentially disease causing mutations in literature-known genes, were present in 18 patients, which accounted for 18.75% of tested cohort. Medium impact variants were also present in KCNA5, TGFBR2, AQP7, BMP6, EIF2AK4, FBP1, NOTCH1, NOTCH3, SMAD7, TBX4, TGFB2, TOPBP1, GDF5, IL6, PPARA, RXRA, KCNK3, KLF4, BMPR1B, ILK, TGFBR1, SMAD9, PPARD and TGFB3 genes. Additionally, in one patient with clinical diagnosis of pulmonary venoocclusive disease we identified an unknown homozygous frameshift variant (p.Phe1523fs/c.4567_4570delTTTG) in exon 35 of EIF2AK4 gene. Conclusions We found potentially disease causing mutations in 18,75% Polish patients diagnosed with IPAH most of them were present in BMPR2 gene which is in line with data from other European cohorts. Additionally we found an unknown mutation in the EIF2AK4 gene. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Narodowe Centrum Nauki - National Science Centre

Clinical genetic analysis and diagnosis of a family with hereditary hemorrhagic telangiectasia

Objective: To explore the diagnostic significance of the combination of clinical and genetic detection of hereditary hemorrhagic telangiectasia (HHT) by analyzing the clinical and genetic diagnosis of a family with HHT. Methods: Medical history data of the probands and their family members were collected, and the sequence analyses of coding regions of ENG, ACVRL1, SMAD4 and GDF2 genes were performed by PCR-sequencing method, and a comprehensive diagnosis was made based on the clinical features and gene detection results. After the pathogenic gene variation was identified, 11 members of 3 generations of the family were tested for pathogenic gene mutation. Results: There was an ACVRL1 c.715_716delAG mutation in the proband and 9 other family members, which caused p.S239C. Based on the clinical and genetic findings, the 7 suspected were diagnosed and 2 asymptomatic patients were found to carry the mutation site. Conclusion: The combination of clinical features and gene detection can determine the etiology and classification of HHT, which is convenient for the early diagnosis and prevention of the disease.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians.MethodsUsing DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review.ResultsIn total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively.ConclusionsIn a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Cyanosis in a Previously Well Child.

Cyanosis in a Previously Well Child.

SIX INCIDENTALLY DISCOVERED IDIOPATHIC PULMONARY ARTERIOVENOUS MALFORMATIONS

TOPIC: Procedures TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary arteriovenous malformations (PAVMs) are rare vascular abnormalities in which arterioles connect directly to venules without passing through a capillary bed. Up to 95% of all PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is an autosomal dominant disease characterized by AVMs most notably affecting the pulmonary, hepatic, and cerebral circulations. Idiopathic PAVMs have a greater propensity to present as solitary malformations. We present the case of a patient with six incidentally discovered PAVMs. Further evaluation, including genetic testing not consistent with HHT, made this an unusual case of multiple presumed idiopathic PAVMs. CASE PRESENTATION: A 34-year-old female with a history of recent left ankle fracture was referred to the pulmonary clinic after an emergency department evaluation revealed six PAVMs on CT pulmonary angiogram following the diagnosis of a left lower extremity deep vein thrombosis. The largest PAVM (2.4 cm) was located in the right upper lobe and was classified as complex, having multiple segmental feeding arteries with a dominant draining vein. The remaining five were classified as simple AVMs, having a single feeding artery and draining vein. She endorsed a history of epistaxis, family history of stroke, and persistent borderline hypoxemia. An anatomic shunt study was performed with arterial blood gas measurements on room air and while breathing 100% oxygen with a calculated shunt fraction of 28%. Transthoracic echocardiogram showed normal pulmonary and central venous pressures. MRI brain revealed multiple punctate foci of enhancement most consistent with small vascular malformations. She underwent genetic testing for HHT (including ACVRL1, ENG, EPHB4, GDF2, RASA1, and SMAD4 genes) which was negative. The patient was referred to Interventional Radiology for coil embolization of the two largest PAVMs given her clinically significant right-to-left shunt. DISCUSSION: PAVMs cause impairment in gas exchange, filtration, and processing of systemic venous blood with a spectrum of clinical manifestations including life-threatening hemorrhage and paradoxical embolism. Although PAVMs are commonly asymptomatic, their unique complications include hypoxemia, dyspnea, hemoptysis, pulmonary hypertension, brain abscess, seizure, and stroke. There is evidence to suggest that idiopathic PAVMs act similarly to HHT-related PAVMs with comparable symptoms and plausible clinical complications. CONCLUSIONS: Clinical presentation may vary widely, however, PAVMs are important to recognize and evaluate for need for intervention, even if asymptomatic, given their potential for serious sequelae if left untreated. REFERENCE #1: Shovlin, CL. Pulmonary Arteriovenous Malformations. Am J Respir Crit Care Med 2014; 190 (11): 1217-28. REFERENCE #2: Wong HH, Chan RP, Klatt R, Faughnan ME: Idiopathic pulmonary arteriovenous malformations: clinical and imaging characteristics. Eur Respir J 2011; 38: 368-75. REFERENCE #3: Kroon S, van den Heuvel DAF, Vos JA, et al. Idiopathic and hereditary haemorrhagic telangiectasia associated pulmonary arteriovenous malformations: comparison of clinical and radiographic characteristics. Clin Radiol. 2021;76(5):394. DISCLOSURES: No relevant relationships by Sarah Kemp, source=Web Response No relevant relationships by Patrick Kicker, source=Web Response

Genetic Profiling of Combined Post-Capillary and Pre-Capillary Pulmonary Hypertension in Left Heart Diseases

Pulmonary hypertension (PH) in left heart diseases (LHD) has been redefined as isolated post-capillary PH (IpcPH) and combined post-capillary and pre-capillary PH (CpcPH). CpcPH's pathophysiology is not well understood. Predisposing constitutional factors may play a role in CpcPH development, as suggested by the variability in the adaptation of the pulmonary circulation to the elevation of pulmonary artery wedge pressure (PAWP). We sought to determine whether a genetic predisposition to CpcPH could be identified, suggesting a common pathway with pulmonary arterial hypertension (PAH). Based on Erasme's hospital right heart catheterization database from January 2007 to January 2015, we selected PH-LHD patients to further identify CpcPH patients. Clinical and hemodynamic variables were used to compare IpcPH to CpcPH patients. A small cohort of CpcPH patients underwent genetic testing for genes predisposing to heritable PAH using a gene panel approach and MLPA analysis. 93 patients presented with PH-LHD, of which 32% met the definition of CpcPH. Clinical data was similar in both IpcPH and CpcPH groups except for higher morphometric features in CpcPH patients. Missense variations of the BMPR2 gene (c.1749C>A, p.Asn583Lys) and of the ENG gene (c.1316A>C, p.Lys439Thr) were identified in one CpcPH patient presenting with heart failure due to dilated cardiomyopathy. Based on current knowledge, both variants were classified as variants of unknown significance (VUS). Our study uncovered genomic variations in the BMPR2 and ENG genes of a CpcPH patient, which may support the concept that a predisposing genetic background could modulate the precapillary component in CpcPH, potentially suggesting common genetic pathways between CpcPH and PAH, although this has to be further confirmed by functional testing, studies in bigger cohorts and with IpcPH control populations.

Abstract No. 398 Pathogenic Variants in the ENG, ACVRL1, SMAD4, and GDF2 genes and Clinical Presentations of hereditary hemorrhagic telangiectasia: Experience from a Single Center of HHT Excellence

Abstract No. 398 Pathogenic Variants in the ENG, ACVRL1, SMAD4, and GDF2 genes and Clinical Presentations of hereditary hemorrhagic telangiectasia: Experience from a Single Center of HHT Excellence

Genetic Diagnosis of Hereditary Hemorrhagic Telangiectasia: Four Novel Pathogenic Variations in Turkish Patients

Aims:Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by telangiectasia, epistaxis, and vascular malformations. Pathogenic mutations were found in ENG, AVCRL1, SMAD4, and GDF genes. In this study, we present our database of patients with hereditary hemorrhagic telangiectasia regarding the phenotype-genotype relations and discuss two novel ENG gene pathogenic variations in two unrelated families.Methods:Next Generation Sequencing analysis was performed on the peripheral blood of nine patients with hereditary hemorrhagic telangiectasia in four unrelated families. All patients were diagnosed with hereditary hemorrhagic telangiectasia according to the Curaçao criteria. Data on treatment and screenings of visceral involvement were recorded from files.Results:We have found a pathogenic variation in either the ENG or ACVRL1 gene in each family. Two novel pathogenic variations in the ENG gene, including NM_000118.3 (ENG): c.416delC (p.P139fs*24) and NM_000118.3(ENG): c.1139dupT (p.Leu380PhefsTer16), were found in the same family. The NM_000020.2(ACVRL1): c.1298C>T (p.Pro433Leu) pathogenic variation in the ACVRL1 gene in our first family and a novel heterozygous likely pathogenic NM_000020.2(ACVRL1): c.95T>C (p.Val32Ala) variation was found in our second family. Seven of the nine patients were treated with thalidomide for controlling bleeding episodes. All patients responded to thalidomide. In one patient, the response to thalidomide was lost and switched to bevacizumab.Conclusion:In hereditary hemorrhagic telangiectasia, certain types of mutations correlate with disease phenotypes and with next generation sequencing methods. New pathogenic variations can be revealed, which might help manage patients with hereditary hemorrhagic telangiectasia.

Genetic diagnostics of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular disease with a worldwide prevalence of 1:5000 - 1:10000. Diagnosis is based on clinical Curacao criteria. Approximately 85% of HHT cases have heterozygous family-specific mutations in the ENG or ACVRL1 genes. Aim: We investigated 23 Hungarian HHT families, established the genetic diagnosis, executed family-screening and confirmed founder effects. Method: Probands were identified by the stratified population screening of the primary attendance area of our institution and from individuals contacting our study group voluntarily. Diagnosis is based on the otorhinolaryngological physical examination completed with characteristic telangiectasis sites, a visceral arteriovenous malformation screening and the sequence analysis of ENG and ACVRL1 genes. The family screening consists of physical examination and genetic screening for the family-specific mutation, followed by the arteriovenous malformation screening in patients with definite/suspected HHT and/or in individuals with the mutation. Results: Sixty-three individuals with family-specific mutations were identified in 22 families, 48 of them with definite and 12 with suspected HHT. Seven ENG and ACVRL1 mutations were detected, respectively; most of these are pathogenic. Three founder mutations were observed. One proband with definite HHT had wild-type alleles in all tested HHT-specific loci. Conclusions: The significance of genetic testing is confirming or excluding HHT in young asymptomatic individuals in families with pathogenic mutations. As ENG and ACVRL1 mutations result in overlapping fenotypes, the genetic testing lacks any prognostic value. The identification of founder effects might simplify the genetic diagnosis of new HHT patients from a given region. Orv Hetil. 2019; 160(18): 710-719.

Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-β/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.

Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients.

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.

Progress in genetic research on primary pulmonary hypertension

Primary pulmonary hypertension (PPH) consisting of hereditary pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension is an obstructive pulmonary hypertension caused by primary pulmonary artery hyperplasia. Both environmental and genetic factors are involved in the pathogenesis of PPH. Genes associated with TGF-β signaling pathway including BMPR2, ALK1, ENG, SMAD8 and other genes including NFU1, CAV1, KCNK3 and TopBPl have been associated with PPH. In this review, the function and mechanism of the above genes in the pathogenesis PPH are summarized.

Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension.

BackgroundWe aimed to provide a set of previously reported PAH‐associated missense and nonsense variants, and evaluate the pathogenicity of those variants.MethodsThe Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH‐associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH‐associated missense and nonsense variants. The pathogenicity of previously reported PAH‐associated missense variants evaluated by using four in silico prediction tools.ResultsIn total, 14 PAH‐associated genes and 180 missense and nonsense variants were gathered. The BMPR2, the most frequent reported gene, encompasses 135 of 180 missense and nonsense variants. The exome sequencing project comprised 9, and the exome aggregation consortium counted 25 of 180 PAH‐associated missense and nonsense variants. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis.ConclusionThis is the first evaluation of previously reported PAH‐associated missense and nonsense variants. The BMPR2 identified as the major gene out of 14 PAH‐associated genes. Based on findings, the ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH.

Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler’s Disease, Uppsala University Hospital

Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT).Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess.Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications.Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.

Gene identification in a family of hereditary hemorrhagic telangiectasia

目的研究一个遗传性出血性毛细血管扩张症（HHT）家系的ENG、ACVRL1、SMAD4基因突变情况，探讨其分子发病机制。方法对1例HHT患者进行临床诊断和家系调查。采集先证者及其长子外周血标本，应用芯片捕获高通量测序法进行ENG、ACVRL1、SMAD4基因分析，对检出的突变以Sanger测序法进行验证。结果71名家系成员中有9名被临床诊断为HHT，均以反复鼻腔出血为主要表现。基因分析结果显示，先证者及其长子ENG基因9号外显子存在框移突变c.1502-1503insGG（p.Gly501GlyfsX18），未检出ACVRL1、SMAD4基因突变。结论ENG基因框移突变c.1502-1503insGG（p.Gly501GlyfsX18）是这个HHT家系致病的遗传学基础。

Executive summary of the 12th HHT international scientific conference.

Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8-11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme-based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure.