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Jamie Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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curacao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in eng or ACVRL1 hht1 and hht2
Genetics in Medicine, 2020Co-Authors: Jamie Mcdonald, Whitney Wooderchakdonahue, Pinar Bayraktoydemir, Desiree Demille, Kevin J WhiteheadAbstract:Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curacao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia. Review of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed. A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0–52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7–60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2–4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7–6.6%) family probands did not have a variant in one of these genes. Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75–85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curacao criteria is highly predictive of a causative variant in either ENG or ACVRL1.
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genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia
Journal of Medical Genetics, 2018Co-Authors: Whitney Wooderchakdonahue, Jamie Mcdonald, Andrew Farrell, Gulsen Akay, Matt Velinder, Peter Johnson, Chad Vansantwebb, Rebecca L Margraf, Eric BriggsAbstract:Introduction Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG , ACVRL1 , and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. Methods DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG , ACVRL1 and SMAD4 . Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. Results Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1 intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich ‘hotspot’ region of ACVRL1 intron 9 that disrupted splicing. Conclusions Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1 intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.
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bmp9 mutations cause a vascular anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia
American Journal of Human Genetics, 2013Co-Authors: Whitney Wooderchakdonahue, Beth L. Roman, Jamie Mcdonald, Brendan D Ofallon, Paul D Upton, Sarah Young, Parker Plant, Gyula T Fulop, Carmen Langa, Nicholas W MorrellAbstract:Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.
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mosaic ACVRL1 and eng mutations in hereditary haemorrhagic telangiectasia patients
Journal of Medical Genetics, 2011Co-Authors: Hunter D Best, Jamie Mcdonald, Cecily P Vaughn, Kristy Damjanovich, James R Runo, Jason M Chibuk, Pinar BayraktoydemirAbstract:Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in the ACVRL1, ENG, and SMAD4 genes. HHT is commonly characterised by small arteriovenous malformations (AVMs) known as telangiectasias of the skin, oral or gastrointestinal mucosa, as well as larger AVMs of solid organs (lungs, liver, brain). However, the manifestations of HHT are extremely variable. Two patients with no family history of HHT and strikingly different clinical presentations, who are mosaic for mutations in the ACVRL1 or ENG gene, are reported here. These cases represent the first report of mosaicism in patients clinically affected with classical HHT and pulmonary arterial hypertension, and suggest the need for awareness of mosaicism when performing clinical testing for this disorder.
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genotype phenotype correlation in hereditary hemorrhagic telangiectasia mutations and manifestations
American Journal of Medical Genetics Part A, 2006Co-Authors: Jamie Mcdonald, Pinar Bayraktoydemir, Boaz A Markewitz, Susan O Lewin, Franklin J Miller, Lanszu Chou, Friederike Gedge, Wei TangAbstract:Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.
Pinar Bayraktoydemir - One of the best experts on this subject based on the ideXlab platform.
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curacao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in eng or ACVRL1 hht1 and hht2
Genetics in Medicine, 2020Co-Authors: Jamie Mcdonald, Whitney Wooderchakdonahue, Pinar Bayraktoydemir, Desiree Demille, Kevin J WhiteheadAbstract:Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curacao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia. Review of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed. A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0–52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7–60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2–4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7–6.6%) family probands did not have a variant in one of these genes. Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75–85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curacao criteria is highly predictive of a causative variant in either ENG or ACVRL1.
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mosaic ACVRL1 and eng mutations in hereditary haemorrhagic telangiectasia patients
Journal of Medical Genetics, 2011Co-Authors: Hunter D Best, Jamie Mcdonald, Cecily P Vaughn, Kristy Damjanovich, James R Runo, Jason M Chibuk, Pinar BayraktoydemirAbstract:Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in the ACVRL1, ENG, and SMAD4 genes. HHT is commonly characterised by small arteriovenous malformations (AVMs) known as telangiectasias of the skin, oral or gastrointestinal mucosa, as well as larger AVMs of solid organs (lungs, liver, brain). However, the manifestations of HHT are extremely variable. Two patients with no family history of HHT and strikingly different clinical presentations, who are mosaic for mutations in the ACVRL1 or ENG gene, are reported here. These cases represent the first report of mosaicism in patients clinically affected with classical HHT and pulmonary arterial hypertension, and suggest the need for awareness of mosaicism when performing clinical testing for this disorder.
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genotype phenotype correlation in hereditary hemorrhagic telangiectasia mutations and manifestations
American Journal of Medical Genetics Part A, 2006Co-Authors: Jamie Mcdonald, Pinar Bayraktoydemir, Boaz A Markewitz, Susan O Lewin, Franklin J Miller, Lanszu Chou, Friederike Gedge, Wei TangAbstract:Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.
Melanie Eyries - One of the best experts on this subject based on the ideXlab platform.
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sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia
Orphanet Journal of Rare Diseases, 2020Co-Authors: Sophie Giraud, Melanie Eyries, Brigitte Gilbertdussardier, Claire Bardel, Sophie Dupuisgirod, M F Carette, S Riviere, Jeanchristophe Saurin, Sylvie PatriAbstract:Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs. We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs. The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
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clinical and genetic characteristics of chinese patients with hereditary haemorrhagic telangiectasia associated pulmonary hypertension
European Journal of Clinical Investigation, 2013Co-Authors: Yanjun Chen, Melanie Eyries, Florent Soubrier, Qinghui Yang, Wenhui Wu, Xin Jiang, Ping Yuan, Rui Zhang, Zhicheng JingAbstract:Background Mutations in activin receptor-like kinase-1 (ACVRL-1) or endoglin (ENG) are mostly identified in patients with hereditary haemorrhagic telangiectasia (HHT) associated with pulmonary hypertension (PH), but have not yet been studied in Chinese patients. Material and methods In this study, we investigated the clinical and molecular genetic features of Chinese patients with HHT-associated PH and analysed genotype/phenotype correlations in 14 probands and their relatives. Mutation analyses in ACVRL-1, bone morphogenetic protein receptor type 2 (BMPR2) and ENG were performed in 14 Chinese Han patients with HHT-associated PH. Results The overall mutation rate was 71·4%, including 8 ACVRL-1 mutations and 2 ENG mutations, 6 of which were novel. Six patients were identified with arteriovenous malformations (AVMs), including four patients with pulmonary AVMs and two patients with liver AVMs. Five of the patients with AVMs were identified with mutations. Most patients received targeted therapy for PH. Conclusions Our findings have revealed the clinical phenotype and molecular genetic features of HHT-associated PH in Chinese Han patients and indicate that mutations of ACVRL-1 and ENG are genetic predisposing factors in Chinese patients. Our data further addressed clinical management and have provided limited experience in treating this group of disorders.
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ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
Clinical Genetics, 2012Co-Authors: Melanie Eyries, Florence Coulet, Barbara Girerd, David Montani, Marc Humbert, P Lacombe, Thierry Chinet, Laurent Gouya, Joelle Roume, Michelle M AxfordAbstract:Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.
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ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
Clinical Genetics, 2012Co-Authors: Melanie Eyries, Florence Coulet, Barbara Girerd, David Montani, Marc Humbert, P Lacombe, Thierry Chinet, Laurent Gouya, Joelle Roume, Michelle M AxfordAbstract:Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.
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genetics of pulmonary arterial hypertension and the concept of heritable pulmonary arterial hypertension
2012Co-Authors: Barbara Girerd, Azzeddine Yaici, Melanie Eyries, Florence Coulet, David Montani, Florent Soubrier, Marc HumbertAbstract:Germline mutations of BMPR2 gene ( bone morphogenetic protein receptor type 2 ), or more rarely of ACVRL1 ( activin A receptor type II-li
Carla Olivieri - One of the best experts on this subject based on the ideXlab platform.
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ACVRL1 activin a receptor type ii like 1
Atlas of genetics and cytogenetics in oncology and haematology, 2014Co-Authors: Federica Ornati, L Vecchia, C Scotti, S Plumitallo, Carla OlivieriAbstract:Activin A receptor, type II-like kinase 1 (ALK1 is a serine-threonine kinase) predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. Its involvement in cancer neoangiogenesis has lead to the recent development of novel anti-cancer drugs, which are now in clinical trials.
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hereditary hemorrhagic telangiectasia breakpoint characterization of a novel large deletion in ACVRL1 suggests the causing mechanism
Molecular Syndromology, 2013Co-Authors: Laura Boeri, Fabio Pagella, Elisabetta Buscarini, Orietta Radi, Cecilia Canzonieri, Agnese Scatigno, Antonella Minelli, Federica Ornati, Cesare Danesino, Carla OlivieriAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10
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hereditary hemorrhagic telangiectasia evidence for regional founder effects of ACVRL1 mutations in french and italian patients
European Journal of Human Genetics, 2008Co-Authors: Gaetan Lesca, Florence Coulet, Sophie Dupuisgirod, Carla Olivieri, Elisabetta Buscarini, Florent Soubrier, Emmanuelle Genin, Claire Blachier, Guy Brunet, Alain CalenderAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.
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analysis of eng and ACVRL1 genes in 137 hht italian families identifies 76 different mutations 24 novel comparison with other european studies
Journal of Human Genetics, 2007Co-Authors: Carla Olivieri, Fabio Pagella, Lucia Semino, Luca Lanzarini, Cristina Valacca, Andrea Pilotto, Sabrina Corno, Susi Scappaticci, Guido Manfredi, Elisabetta BuscariniAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder causing vascular dysplasias. About 70–80% of HHT patients carries mutations in ENG or ACVRL1 genes, which code for a TGFβ receptor type III and I respectively. Molecular data on a large cohort of Italian HHT patients are presented, discussing the significance of missense and splice site mutations. Mutation analysis in ENG and ACVRL1 genes was performed using single strand conformation polymorphisms (SSCP), denaturing high performance liquid chromatography (DHPLC) and subsequent direct sequencing. Overall, 101 mutations were found, with ACVRL1 involved in 71% of cases. The highest number of mutations (28/101 subjects, 14/76 different mutations referring to both genes) was in ACVRL1, exon 3. Mutation analysis was then extended to a total of 356 family members, and 162 proven to carry the mutation. New polymorphisms were identified in both genes, and evidence that ENG P131L change is not a disease-causing mutation was also provided. An in silico analysis was performed in order to characterize splice-site mutations. These results were compared to other European national studies and data from Italy, France and Spain were consistent for an higher incidence of ACVRL1 mutations.
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identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected italian patients affected by hereditary haemorrhagic telangiectasia
Journal of Medical Genetics, 2002Co-Authors: Carla Olivieri, E Mira, G Delu, F Pagella, A Zambelli, L Malvezzi, E Buscarini, Cesare DanesinoAbstract:Hereditary haemorrhagic telangiectasia (HHT) (OMIM 187300) is an autosomal dominant disorder caused by mutations in either of two genes, endoglin ( ENG , OMIM 131195) (HHT1) and activin A receptor type II-like 1 ( ACVRL1 , OMIM 601284) (HHT2). Evidence for a third locus has also been reported.1 The product of the ACVRL1 gene is a type I receptor for the TGF-beta group of ligands; it is associated with the TGF-beta or activin type II receptors and the complex binds TGF-beta or activin. It is highly expressed in endothelial cells, lung, and placenta, as endoglin, mutations of which are observed in HHT1; endoglin is supposed to sequester TGF-beta and present the ligand to activin A receptor type II-like 1 plus a type II receptor.2 Mutations in ENG and ACVRL1 may cause HHT1 or HHT2, respectively, by disrupting this complex. The clinical presentation, indistinguishable between HHT1 and HHT2, typically includes epistaxis and telangiectasia, and the diagnosis can be considered to be confirmed, according to the proposal of Shovlin et al ,3 if three of the four suggested diagnostic criteria (epistaxis, telangiectasia, visceral lesions, positive family history) are present. The phenotype is highly variable and penetrance is complete by the age of 40 years.4 Arteriovenous (AV) fistulae are frequently observed in the liver (8% of patients),5 lungs (20%),6 and brain5 and may cause severe life threatening complications. Neurological complications (strokes, cerebral abscesses, seizures) may be prevented with appropriate treatment of the pulmonary arteriovenous malformations (PAVMs). A higher risk for lung involvement has been suggested in patients carrying mutations in the ENG gene,7 while in some families with a peculiar liver involvement, mutations in ACVRL1 have been described.8 The involvement of the latter gene has also been reported in a single patient with a pituitary tumour …
Florence Coulet - One of the best experts on this subject based on the ideXlab platform.
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ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
Clinical Genetics, 2012Co-Authors: Melanie Eyries, Florence Coulet, Barbara Girerd, David Montani, Marc Humbert, P Lacombe, Thierry Chinet, Laurent Gouya, Joelle Roume, Michelle M AxfordAbstract:Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.
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ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
Clinical Genetics, 2012Co-Authors: Melanie Eyries, Florence Coulet, Barbara Girerd, David Montani, Marc Humbert, P Lacombe, Thierry Chinet, Laurent Gouya, Joelle Roume, Michelle M AxfordAbstract:Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.
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genetics of pulmonary arterial hypertension and the concept of heritable pulmonary arterial hypertension
2012Co-Authors: Barbara Girerd, Azzeddine Yaici, Melanie Eyries, Florence Coulet, David Montani, Florent Soubrier, Marc HumbertAbstract:Germline mutations of BMPR2 gene ( bone morphogenetic protein receptor type 2 ), or more rarely of ACVRL1 ( activin A receptor type II-li
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Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation
American Journal of Respiratory and Critical Care Medicine, 2010Co-Authors: Barbara Girerd, Benjamin Sztrymf, Azzeddine Yaici, David Tregouet, Abilio Reis, Xavier Jais, Florence Coulet, David Montani, Valérie Drouin-garraudAbstract:Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH).Objectives: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation.Methods: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database.Measurements and Main Results: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 ± 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 ± 14.9 and 47.6 ± 16...
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hereditary hemorrhagic telangiectasia evidence for regional founder effects of ACVRL1 mutations in french and italian patients
European Journal of Human Genetics, 2008Co-Authors: Gaetan Lesca, Florence Coulet, Sophie Dupuisgirod, Carla Olivieri, Elisabetta Buscarini, Florent Soubrier, Emmanuelle Genin, Claire Blachier, Guy Brunet, Alain CalenderAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.