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1. uAUG creating variants in the 5’UTR of ENG causing Hereditary Hemorrhagic Telangiectasia

Author: Omar Soukarieh, Emmanuelle Tillet, Carole Proust, Charlène Dupont, Béatrice Jaspard-Vinassa, Florent Soubrier, Aurélie Goyenvalle, Mélanie Eyries, and David-Alexandre Trégouët
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two variants, c.-79C>T and c.-68G>A, in the 5’UTR of ENG in two unrelated patients. They create upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon. To assess the pathogenicity of these variants, we performed functional assays based on the expression of wild-type and mutant constructs in human cells and evaluated their effect on ALK1 activity in a BMP-response element assay. This assay is mandatory for molecular diagnosis and has been so far only applied to coding ENG variants. These variants were associated with a decrease of protein levels in HeLa and HUVEC cells and a decreased ability to activate ALK1. We applied the same experiments on three additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) located in the 5’UTR of ENG and previously reported in HHT patients. We found that all the analyzed variants alter protein levels and function. Additional experiments relying on an artificial deletion in our mutated constructs show that identified uAUGs could initiate the translation indicating that the associated effect is translation-dependent. Overall, we have identified two 5’UTR ENG variations in HHT patients and shed new light on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.
Published: 2023
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2. Outcomes and risk assessment in pulmonary veno-occlusive disease

Author: Athénaïs Boucly, Sabina Solinas, Antoine Beurnier, Xavier Jaïs, Sophia Keddache, Mélanie Eyries, Andrei Seferian, Mitja Jevnikar, Anne Roche, Sophie Bulifon, Arnaud Bourdin, Ari Chaouat, Vincent Cottin, Laurent Bertoletti, Laurent Savale, Marc Humbert, Olivier Sitbon, and David Montani
Subjects: Medicine
Abstract: Introduction Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. Methods The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Results Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. Conclusion PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.
Published: 2024
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3. Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype

Author: Berivan Tas, Daniele Starnoni, Stanislas Smajda, Alexandre J. Vivanti, Catherine Adamsbaum, Mélanie Eyries, Judith Melki, Marcel Tawk, Augustin Ozanne, Nicole Revencu, Florent Soubrier, Selima Siala, Miikka Vikkula, Kumaran Deiva, and Guillaume Saliou
Subjects: vein of Galen aneurysmal malformation, cerebral arteriovenous fistula, arteriovenous shunt (AVS), Rendu-Osler-Weber disease, RASA1 mutation, EPHB4 mutation, Pediatrics, RJ1-570
Abstract: ObjectiveTo study the genotypes and phenotypes of cerebral arteriovenous fistulas that drain or do not drain through the vein of Galen, and true vein of Galen aneurysmal malformations, in order to determine whether genotyping could help improve classification of these malformations and their management.MethodsWe carried out a retrospective review of genetic and phenotypic data in databases of four centers. All children with cerebral arteriovenous fistula or vein of Galen aneurysmal malformations aged below 18 years at onset were included. We recorded the nature of the genetic variant or absence of variant, age at onset, type of malformation, symptoms at onset (hemorrhage, neurological deficit, hydrocephalus, incidental, and heart failure), type of venous drainage and the long-term outcome.ResultsOne hundred and fifteen children were included. Autosomal dominant variants were identified in 39% of patients. The most frequent variant affected was the RASA1 gene (25%) followed by EPHB4 (8%) and the HHT-associated genes (5%). HHT gene variants were only observed in pial arteriovenous fistula not draining into the vein of Galen; on the contrary, EPHB4 variants were only seen in genuine vein of Galen aneurysmal malformation. RASA1 variants were identified in all types of shunts.ConclusionsEPHB4 variants seem specific to the vein of Galen aneurysmal malformation, RASA1 variants are associated with either pial arteriovenous fistulas or with genuine VGAM and HHT gene variants seem specific to pial arteriovenous fistulas. The genetic data helps to classify these malformations and to guide treatment toward lowest risk of post-operative cerebral ischemic-hemorrhagic complications.
Published: 2022
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4. Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics

Author: Omar Soukarieh, Caroline Meguerditchian, Carole Proust, Dylan Aïssi, Mélanie Eyries, Aurélie Goyenvalle, and David-Alexandre Trégouët
Subjects: open reading frame (ORF), genome wide association analysis (GWAS), Mendelian disease, non-coding mutations, polymorphism, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in the identification of genetic variations contributing to the risk of rare (Mendelian) and common (multifactorial) human diseases. So far, they have led to numerous successes in identifying rare disease-causing mutations in coding regions, but few in non-coding regions that include introns, untranslated (UTR), and intergenic regions. One class of neglected non-coding variations is that of 5′UTR variants that alter upstream open reading frames (upORFs) of the coding sequence (CDS) of a natural protein coding transcript. Following a brief summary of the molecular bases of the origin and functions of upORFs, we will first review known 5′UTR variations altering upORFs and causing rare cardiovascular disorders (CVDs). We will then investigate whether upORF-affecting single nucleotide polymorphisms could be good candidates for explaining association signals detected in the context of genome-wide association studies for common complex CVDs.
Published: 2022
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5. Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia

Author: Sophie Giraud, Claire Bardel, Sophie Dupuis-Girod, Marie-France Carette, Brigitte Gilbert-Dussardier, Sophie Riviere, Jean-Christophe Saurin, Mélanie Eyries, Sylvie Patri, Evelyne Decullier, Alain Calender, and Gaëtan Lesca
Subjects: HHT, Rendu-Osler, ACVRL1, Modifier gene, Hepatic arteriovenous malformation, Medicine
Abstract: Abstract Background 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. Methods 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. Results 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). Conclusions 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.
Published: 2020
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6. Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors.

Author: Jacques Sellier, Carma Karam, Alain Beauchet, Axel Dallongeville, Stephen Binsse, Sandra Blivet, Isabelle Bourgault-Villada, Philippe Charron, Thierry Chinet, Mélanie Eyries, Carole Fagnou, Jérome Lesniak, Gilles Lesur, Jérome Lucas, Agnès Nicod-Tran, Augustin Ozanne, Aurélien Palmyre, Florent Soubrier, Mostafa El Hajjam, and Pascal Lacombe
Subjects: Medicine, Science
Abstract: BACKGROUND:Splenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT. METHODS:We analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement. RESULTS:SAA concerned 24.7% of HHT patients and 5.4% of controls, p
Published: 2020
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7. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Author: Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath, and Nicholas W. Morrell
Subjects: Science
Abstract: Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.
Published: 2018
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8. Whole-genome sequencing of patients with rare diseases in a national health system.

Author: Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V. V. Deevi, Timothy J. Aitman, David L. H. Bennett, Paul Calleja, Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B. A. Roy, Moin A. Saleem, Kenneth G. C. Smith, Hannah Stark, Rhea Y. Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, Agnieszka Bierzynska, Tina Biss, Maria A. K. Bitner-Glindzicz, Graeme C. M. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Ruth Casey, Jenny Chambers, John Chambers, Melanie M. Y. Chan, Calvin Cheah, Floria Cheng, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R. P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart A. Cook, H. Terence Cook, Nichola Cooper, Paul A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Sofia Douzgou, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S. A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C. Houweling, Luke S. G. E. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sarah Hunter, Matthew E. Hurles, Melita Irving, Louise Izatt, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Fiona Lalloo, Michele Lambert, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Kevin J. Marchbank, Stephen Marks, Hanns-Ulrich Marschall, Andrew G. Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O'Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S. Helen Oram, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry 0003, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E. S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Tara Renton, Christopher J. Rhodes, Andrew S. C. Rice, Alex Richter, Leema Robert, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Nilesh J. Samani, Crina Samarghitean, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A. Carrock Sewell, Denis Seyres, Neil Shah, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Charles A. Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Ellen Thomas, David Thomas 0004, Moira J. Thomas, Patrick Thomas, Kate Thomson, Glen Threadgold, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng-Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Wojciech Turek, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk-Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Christopher Watt, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, John Wharton, Deborah Whitehorn, Andrew O. M. Wilkie, Brian T. Wilson, Edwin K. S. Wong, Nicholas W. Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F. K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, and Eliska Zlamalova
Published: 2020
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9. Molecular Function and Contribution of TBX4 in Development and Disease

Author: Justyna A. Karolak, Carrie L. Welch, Christian Mosimann, Katarzyna Bzdęga, James D. West, David Montani, Mélanie Eyries, Mary P. Mullen, Steven H. Abman, Matina Prapa, Stefan Gräf, Nicholas W. Morrell, Anna R. Hemnes, Frédéric Perros, Rizwan Hamid, Malcolm P. O. Logan, Jeffrey Whitsett, Csaba Galambos, Paweł Stankiewicz, Wendy K. Chung, and Eric D. Austin
Subjects: Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published: 2023

10. Isolated Pulmonary Arteriovenous Malformations Associated With BMPR2 Pathogenic Variants

Author: Mithum Kularatne, Mélanie Eyries, Laurent Savale, Marc Humbert, and David Montani
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published: 2023

11. Detection of a pathogenic Alu element insertion in PALB2 gene from targeted NGS diagnostic data

Author: Mélanie Eyries, Olivier Ariste, Gaelle Legrand, Noémie Basset, Erell Guillerm, Alexandre Perrier, Caroline Duros, Odile Cohen-Haguenauer, Pierre de la Grange, and Florence Coulet
Subjects: Ovarian Neoplasms, Alu Elements, Genetics, High-Throughput Nucleotide Sequencing, Humans, Breast Neoplasms, Female, Fanconi Anemia Complementation Group N Protein, Genetics (clinical), Retrospective Studies
Abstract: Despite routine analysis of a large panel of genes, pathogenic variants are only detected in approximately 20% of families with hereditary breast and/or ovarian cancer. Mobile element insertions (MEI) are known to cause genetic diseases in humans, but remain challenging to detect. Retrospective analysis of targeted next-generation sequencing (NGS) data from 359 patients was performed using a dedicated MEI detection pipeline. We detected one MEI in exon 9 of the PALB2 gene in a woman with a family history of breast cancer. The pathogenic variant, c.2872_2888delins114AluL2, disrupts the PALB2 coding sequence and leads to the production of a truncated protein, p.(Gln958Valfs*38). This is the first report of a pathogenic MEI in PALB2. This study illustrates that MEI analysis may help to improve molecular diagnostic yield and can be performed from targeted NGS data used for routine diagnosis.
Published: 2022

12. Novel uAUG creating variants in the 5’UTR of ENG causing Hereditary Hemorrhagic Telangiectasia

Author: Omar Soukarieh, Emmanuelle Tillet, Carole Proust, Charlène Dupont, Béatrice Jaspard-Vinassa, Florent Soubrier, Aurélie Goyenvalle, Mélanie Eyries, and David-Alexandre Trégouët
Abstract: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare vascular disorder causing abnormal vessel formation and characterized by autosomal dominant transmission. The associated considerable variability in symptoms and clinical severity complicate the management of the disease. In clinical routine, 3 main genes,ACVRL1(also known asALK1),ENGandSMAD4are screened for pathogenic variants at the origin of HHT. About 80% of HHT cases are caused by pathogenic coding variants inACVRL1andENG. However, at least 15% remain with no molecular explanations in the 3 main genes. We here report the identification of 2 never reported variants, c.-79C>T and c.-68G>A, in the 5’UTR ofENGin 2 unrelated HHT patients. These 2 variants are predicted to create upstream AUGs (uAUGs) in the 5’UTR, which are in frame with a stop codon located within the CoDing Sequence (CDS), thus generating Overlapping upstream Open reading frames (uoORFs). In other cases, uAUGs can lead to fully upstream ORFs (uORFs) when associated with stop codons located within the 5’UTR or to elongated CDS (eCDS) when in frame with the CDS and associated with the main stop codon.In order to assess the pathogenicity of theseENGvariants, we performedin vitrofunctional assays based on the expression of wild-type and mutant constructs in human cells. We found that these 5’UTRENGvariants were associated with a decrease of protein levels in HeLa and HUVEC cells. They were also associated with a decreased ability to activate BMP9-stimulated ALK1 receptor in a BMP-response element (BRE) assay. This assay is a mandatory element before providing a definitive molecular diagnosis and has been so far applied only on codingENGvariants. We applied the same experimental workflow on 3 additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) and one eCDS-creating variant (c.-9G>A) in the 5’UTR ofENGpreviously reported in HHT patients. We found that all the analysed uoORF-creating variants alter endoglin levels and function. A comparison of our experimental results with patients’ clinical characteristics suggests that uoORF-creating variants leading to ENG protein levels ≤ 40%in vitrowould be associated with HHT. Additional experiments relying on an artificial deletion in our mutated constructs show that created uAUGs predicted to create uoORFs are able to initiate the translation indicating that the associated effect is likely caused by an alteration of the translation mechanism.Overall, we here identified two never reported 5’UTRENGvariations in HHT patients and shed new lights on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.
Published: 2022

13. Molecular Function and Contribution of

Author: Justyna A, Karolak, Carrie L, Welch, Christian, Mosimann, Katarzyna, Bzdega, James D, West, David, Montani, Mélanie, Eyries, Mary P, Mullen, Steven H, Abman, Matina, Prapa, Stefan, Gräf, Nicholas W, Morrell, Anna R, Hemnes, Frédéric, Perros, Rizwan, Hamid, Malcolm P O, Logan, Jeffrey, Whitsett, Csaba, Galambos, Paweł, Stankiewicz, Wendy K, Chung, and Eric D, Austin
Abstract: Over the past decade recognition of the profound impact of the T-box 4 (TBX4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, upon respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption impacts development.
Published: 2022

14. Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Author: Nicole Revencu, Astrid Eijkelenboom, Claire Bracquemart, Pia Alhopuro, Judith Armstrong, Eulalia Baselga, Claudia Cesario, Maria Lisa Dentici, Melanie Eyries, Sofia Frisk, Helena Gásdal Karstensen, Nagore Gene-Olaciregui, Sirpa Kivirikko, Cinzia Lavarino, Inger-Lise Mero, Rodolphe Michiels, Elisa Pisaneschi, Bitten Schönewolf-Greulich, Ilse Wieland, Martin Zenker, and Miikka Vikkula
Subjects: ERN, Gene curation, ISSVA, Mosaic, Precision medicine, Postzygotic, Medicine
Abstract: Abstract Background Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. Results Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene–disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene–phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. Conclusions This work provides a detailed evidence-based view of the gene–disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene–phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).
Published: 2024
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15. Screening for pulmonary veno-occlusive disease in heterozygous

Author: Benoit, Lechartier, Barbara, Girerd, Mélanie, Eyries, Antoine, Beurnier, Marc, Humbert, and David, Montani
Subjects: Heterozygote, Hypertension, Pulmonary, Humans, Pulmonary Veno-Occlusive Disease, Protein Serine-Threonine Kinases
Published: 2022

16. An emerging phenotype of pulmonary arterial hypertension patients carrying

Author: David, Montani, Benoit, Lechartier, Barbara, Girerd, Mélanie, Eyries, Maria-Rosa, Ghigna, Laurent, Savale, Xavier, Jaïs, Andrei, Seferian, Mitja, Jevnikar, Athénais, Boucly, Marianne, Riou, Julie, Traclet, Ari, Chaouat, Maryline, Levy, Jerome, Le Pavec, Elie, Fadel, Frédéric, Perros, Florent, Soubrier, Martine, Remy-Jardin, Olivier, Sitbon, Damien, Bonnet, and Marc, Humbert
Abstract: The phenotype of pulmonary arterial hypertension (PAH) patients carryingWe report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carryingTwenty patients and eight unaffected relatives were identified. The median (min-max) age at diagnosis was 17 years (2-53), with a female-to-male ratio of 1.5. At diagnosis, most of the patients (74%) were in functional class III or IV with severe hemodynamic compromise, including a median pulmonary vascular resistance (PVR) of 14.0 (4.2-31.5) Wood units (WU). An associated congenital heart disease (CHD) was found in 7 PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. Thirteen out of 16 patients (81%) of whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as bronchial and non-bronchial arteries anomalies. After a median follow-up of 47 months (1-591 months), 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathologic analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci.PAH due to
Published: 2022

17. Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype

Author: Berivan, Tas, Daniele, Starnoni, Stanislas, Smajda, Alexandre J, Vivanti, Catherine, Adamsbaum, Mélanie, Eyries, Judith, Melki, Marcel, Tawk, Augustin, Ozanne, Nicole, Revencu, Florent, Soubrier, Selima, Siala, Miikka, Vikkula, Kumaran, Deiva, Guillaume, Saliou, and UCL - SSS/DDUV/GEHU - Génétique
Subjects: arteriovenous shunt (AVS), vein of Galen aneurysmal malformation, cerebral arteriovenous fistula, cardiovascular system, EPHB4 mutation, Perinatology and Child Health, Rendu-Osler-Weber disease, Pediatrics, RASA1 mutation
Abstract: To study the genotypes and phenotypes of cerebral arteriovenous fistulas that drain or do not drain through the vein of Galen, and true vein of Galen aneurysmal malformations, in order to determine whether genotyping could help improve classification of these malformations and their management. We carried out a retrospective review of genetic and phenotypic data in databases of four centers. All children with cerebral arteriovenous fistula or vein of Galen aneurysmal malformations aged below 18 years at onset were included. We recorded the nature of the genetic variant or absence of variant, age at onset, type of malformation, symptoms at onset (hemorrhage, neurological deficit, hydrocephalus, incidental, and heart failure), type of venous drainage and the long-term outcome. One hundred and fifteen children were included. Autosomal dominant variants were identified in 39% of patients. The most frequent variant affected was the gene (25%) followed by (8%) and the HHT-associated genes (5%). HHT gene variants were only observed in pial arteriovenous fistula not draining into the vein of Galen; on the contrary, variants were only seen in genuine vein of Galen aneurysmal malformation. variants were identified in all types of shunts. variants seem specific to the vein of Galen aneurysmal malformation, variants are associated with either pial arteriovenous fistulas or with genuine VGAM and HHT gene variants seem specific to pial arteriovenous fistulas. The genetic data helps to classify these malformations and to guide treatment toward lowest risk of post-operative cerebral ischemic-hemorrhagic complications.
Published: 2022

18. Author response for 'A CELSR1 variant in a patient with pulmonary arterial hypertension'

Author: Barbara Girerd, Marc Humbert, Florent Soubrier, David Montani, Laurent Savale, and Mélanie Eyries
Published: 2021

19. First histological description of pulmonary and vascular abnormalities of pulmonary hypertension associated withKDRpathogenic variant

Author: Marianne Riou, Matthieu Canuet, Maria-Rosa Ghigna, Mélanie Eyries, Marie Pierrette Chenard, Michele Porzio, Anne Olland, Marc Humbert, Romain Kessler, and David Montani
Subjects: Pulmonary and Respiratory Medicine
Published: 2022

20. Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

Author: Sven Günther, Laurent Savale, Sébastien Hascoët, Mélanie Eyries, Pierantonio Laveneziana, Florent Soubrier, Gérald Simonneau, Olivier Sitbon, Edmund M.T. Lau, Marc Humbert, Antoine Beurnier, Philippe Hervé, Barbara Girerd, Amir Bouchachi, Florence Parent, Denis Chemla, David Montani, Christophe Guignabert, Laurent Godinas, Xavier Jaïs, Hôpital Bicêtre, Pôle des Cardiopathies Congénitales du Nouveau-Né à L'adulte - Centre Constitutif Cardiopathies Congénitales Complexes M3C, Groupe Hospitalier Paris Saint-Joseph, Hôpital Marie-Lannelongue, Inserm U999, Université Paris-Saclay, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département Médico-Universitaire APPROCHES, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Royal Prince Alfred Hospital [Camperdown, Australia] (RPAH), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Laveneziana, Pierantonio, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Prince Alfred Hospital [Sydney, Australia], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and HAL-SU, Gestionnaire
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary function testing, 0302 clinical medicine, Risk Factors, Original Research Articles, Familial Primary Pulmonary Hypertension, Stage (cooking), 0303 health sciences, education.field_of_study, Pulmonary Arterial Hypertension, Incidence (epidemiology), 06 humanities and the arts, 060202 literary studies, Brain natriuretic peptide, 3. Good health, [SDV] Life Sciences [q-bio], 0602 languages and literature, Screening, Female, medicine.symptom, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Hypertension, Pulmonary, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Protein Receptors, Type II, Asymptomatic, 03 medical and health sciences, Physicians, Internal medicine, Genetics, medicine, Humans, education, 030304 developmental biology, Pulmonary Vascular Disease, Genetic counselling, business.industry, BMPR2, medicine.disease, Pulmonary hypertension, Annual Screening, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030228 respiratory system, Mutation, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: Background Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. Methods Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. Results 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. Conclusions Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH., Asymptomatic BMPR2 mutation carriers have a 2.3% per year risk of developing PAH. DELPHI-2 provides the platform for future international multicentre studies to refine multimodal screening algorithms in BMPR2 mutation carriers. http://bit.ly/3oi2KJ1
Published: 2021

21. Correction to: Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Author: Nicole Revencu, Astrid Eijkelenboom, Claire Bracquemart, Pia Alhopuro, Judith Armstrong, Eulalia Baselga, Claudia Cesario, Maria Lisa Dentici, Melanie Eyries, Sofia Frisk, Helena Gásdal Karstensen, Nagore Gene‑Olaciregui, Sirpa Kivirikko, Cinzia Lavarino, Inger‑Lise Mero, Rodolphe Michiels, Elisa Pisaneschi, Bitten Schönewolf‑Greulich, Ilse Wieland, Martin Zenker, and Miikka Vikkula
Subjects: Medicine
Published: 2024
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22. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports

Author: Florent Soubrier, Augustin Ozanne, Mostafa El Hajjam, Thierry Chinet, Aurélien Palmyre, Mélanie Eyries, Isabelle Bourgault Villada, Robert Carlier, Ahmed Mekki, Hôpital Ambroise Paré [AP-HP], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Raymond Poincaré [AP-HP]
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Portocaval shunt, business.industry, [SDV]Life Sciences [q-bio], Mucocutaneous zone, 030105 genetics & heredity, Endoglin, Phenotype, 3. Good health, Cerebral arteriovenous malformations, 03 medical and health sciences, 030104 developmental biology, cardiovascular medicine, Mothers against decapentaplegic homolog 4, otorhinolaryngologic diseases, Genetics, Medicine, Medical genetics, Radiology, business, clinical genetics, Genetics (clinical), Hereditary haemorrhagic telangiectasia
Abstract: Background We report two cases of RASA1-related capillary malformation-arteriovenous malformation (CM-AVM1) syndrome mimicking hereditary haemorrhagic telangiectasia (HHT).Methods and results A 28-year-old man, previously embolised for cerebral arteriovenous malformations (AVMs), presented with epistaxis and typical nasal telangiectasias of HHT. CT scan revealed a large portocaval shunt. The second patient was a 9-year-old girl presenting with cyanosis and several mucocutaneous telangiectasias, similar to those observed in typical cases of HHT. CT scan revealed a huge and complex pulmonary AVM of the right lower lobe and a hepatic AVM within the left lobe. HHT diagnosis was considered possible according to the Curaçao criteria for the two patients, with at least two criteria for each. Genetic tests did not find any mutation in the three classic genes (Endoglin, Activin receptor-like kinase 1 or Mothers against decapentaplegic homolog 4), but identified in both cases an RASA1 mutation, known to cause CM-AVM1 syndrome.Conclusions Pulmonary AVM and portocaval shunt, usually encountered in HHT, have not yet been described in the CM-AVM1 syndrome. RASA1 screening may be considered in case of HHT suspicion, particularly when mutations are not found in the usually affected genes.
Published: 2020

23. A <scp>CELSR1</scp> variant in a patient with pulmonary arterial hypertension

Author: Mélanie Eyries, Florent Soubrier, David Montani, Marc Humbert, Barbara Girerd, and Laurent Savale
Subjects: medicine.medical_specialty, business.industry, Internal medicine, Genetics, medicine, Cardiology, MEDLINE, business, Genetics (clinical)
Published: 2021

24. Congenital vascular lesions, could MAPK and PI3K inhibitors pave the way to new therapies?

Author: Olivia Boccara, Mélanie Eyries, and Annouk Bisdorff-Bresson
Subjects: 0301 basic medicine, MAPK/ERK pathway, Cancer Research, Functional impairment, MAP Kinase Signaling System, medicine.medical_treatment, Bioinformatics, Targeted therapy, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, medicine, Sclerotherapy, Animals, Humans, Molecular Targeted Therapy, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Repurposing, Sirolimus, business.industry, TOR Serine-Threonine Kinases, Vascular Neoplasms, 030104 developmental biology, Lymphatic system, Oncology, 030220 oncology & carcinogenesis, ras Proteins, Mitogen-Activated Protein Kinases, business, Proto-Oncogene Proteins c-akt, medicine.drug
Abstract: Purpose of review Superficial vascular anomalies are a heterogeneous group of malformative and tumoral lesions, developed from various types of abnormal lymphatic and/or blood vessels. They are mostly benign but their clinical evolution can lead to dramatic cosmetic concern, functional impairment and even life-threatening conditions. Until recently, treatments relied on invasive procedures such as embotherapy/sclerotherapy and/or surgery. Recent molecular findings pave the way of new medical therapies. Recent findings Two main signaling pathways PI3K-AKT-mTOR and RAS-MAPK-ERK are now identified to encounter for the causative pathogenic genetic variants of most vascular anomalies. Involved genes are also responsible for several common neoplasms for which targeted therapies are already available or under development. Repurposing treatment strategy is considered for vascular anomalies treatment with promising results. Summary The mTOR inhibitor sirolimus is the most used targeted therapy so far but new molecules are tested currently.
Published: 2021

25. Une maladie veino-occlusive pulmonaire familiale avec mutation biallélique hétérozygote composite d’EIF2AK4

Author: Mélanie Eyries, Anne Guillaumot, J.-F. Chabot, Emmanuel Gomez, A. Chaouat, I. Petit, G. Treffel, Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and Service de Radiologie [CHRU Nancy]
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Disease, medicine.disease, Pulmonary hypertension, 3. Good health, Hypoxemia, 03 medical and health sciences, 0302 clinical medicine, Clinical research, 030228 respiratory system, Internal medicine, medicine, Palpitations, Cardiology, Lung transplantation, 030212 general & internal medicine, Pulmonary Veno-Occlusive Disease, Stage (cooking), medicine.symptom, business
Abstract: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Heritable and sporadic forms have been distinguished. Hypoxemia, profound reduction in the diffusion of carbon monoxide and haemodynamic confirmation of pre-capillary pulmonary hypertension are the major diagnostic criteria. Thoracic CT scanning and a response to pharmaceutical therapy provide additional information to confirm the diagnosis. A 52-year-old patient, three of whose siblings had pulmonary hypertension, was admitted with dyspnoea, malaise and palpitations. Right heart catheterisation confirmed pre-capillary pulmonary hypertension. A search for an EIF2AK4 mutation was carried out, and this showed a composite biallelic heterozygous mutation compatible with the diagnosis of familial PVOD, identical to that showed in one of his brothers. Given the signs of severity of the disease and the diagnosis of PVOD, whose response to pharmaceutical therapy is often poor, the patient was placed on a waiting list for lung transplantation. Despite a similar diagnosis in 3 brothers and follow-up proposed 11 years before the diagnosis, pulmonary hypertension appeared within a few weeks and led immediately to a severe clinical situation. Annual clinical and echocardiographic monitoring had been strongly advised to the patient, but had not allowed diagnosis at a mild or moderate stage of the disease. This clinical case shows that the identification of factors predicting the development of heritable PVOD at a pre-symptomatic stage is an important issue for clinical research.
Published: 2020

26. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020

27. Hepatic Arteriovenous Malformation: The Search for a PTEN Mutation!

Author: Daniel Cherqui, Didier Samuel, Audrey Coilly, Mélanie Eyries, Jean-Charles Duclos-Vallée, Maïté Lewin, Oriana Ciacio, Lea Duhaut, Cyrille Feray, Teresa Antonini, Catherine Guettier, and Ilias Kounis
Subjects: Hepatology, biology, business.industry, Activin Receptors, Type II, DNA Mutational Analysis, PTEN Phosphohydrolase, Ascites, Middle Aged, Liver Transplantation, Arteriovenous Malformations, Text mining, Liver, Mutation (genetic algorithm), Cancer research, biology.protein, Medicine, PTEN, Humans, Hepatic arteriovenous malformation, Female, Genetic Testing, business, Hamartoma Syndrome, Multiple, Germ-Line Mutation
Published: 2020

28. Parkes‐Weber syndrome related to RASA1 mosaic mutation

Author: Sonia Ariche-Maman, Mélanie Eyries, Florence Coulet, Olivia Boccara, Stéphanie Pannier, Smail Hadj-Rabia, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)
Subjects: Genetics, 0303 health sciences, [SDV]Life Sciences [q-bio], Mosaic (geodemography), 030204 cardiovascular system & hematology, Biology, medicine.disease, Parkes Weber syndrome, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mutation (genetic algorithm), medicine, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2020

29. Author response for '<scp>Parkes‐Weber</scp> syndrome related to <scp> RASA1 </scp> mosaic mutation'

Author: Olivia Boccara, Florence Coulet, Smail Hadj-Rabia, Mélanie Eyries, Sonia Ariche-Maman, and Stéphanie Pannier
Subjects: Genetics, Mutation (genetic algorithm), medicine, Mosaic (geodemography), Biology, medicine.disease, Parkes Weber syndrome
Published: 2020

30. Screening of pulmonary arterial hypertension in BMPR2 mutation carriers

Author: Laurent Godinas, Christophe Guiganbert, David Montani, Gilles Garcia, Edmund M.T. Lau, Laurent Savale, Xavier Jaïs, Gérald Simonneau, Sébastien Hascoët, Amir Bouchachi, Sven Günther, Olivier Sitbon, Marc Humbert, Mélanie Eyries, Philippe Hervé, Florent Soubrier, Florence Parent, Denis Chemla, Pierantonio Laveneziana, and Barbara Girerd
Subjects: medicine.medical_specialty, medicine.drug_class, business.industry, Incidence (epidemiology), medicine.disease, Asymptomatic, Pulmonary hypertension, Annual Screening, BMPR2, Pulmonary function testing, Internal medicine, Mutation (genetic algorithm), Natriuretic peptide, medicine, Cardiology, medicine.symptom, business
Abstract: Introduction: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene (encoding Bone Morphogenetic Protein Receptor type II). Despite the lack of clear evidence, asymptomatic BMPR2 mutation carriers are recommended to undergo annual screening echocardiography for early detection of PAH. Objectives: To evaluate the utility of a comprehensive multimodal PAH screening program in asymptomatic adult BMPR2 mutation carriers. Methods: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of two years (DELPHI-2 study, NCT01600898). Annual screening included clinical assessment, electrocardiogram, pulmonary function tests, 6-minute walk distance, cardiopulmonary exercise test (CPET), chest x-ray, echocardiography and N-terminal pro-brain natriuretic peptide level. Right heart catheterization (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. Results: Fifty-five subjects (26 males, median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT pro-BNP levels. All subjects accepted RHC at inclusion which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension of unknown significance (21.8%). At long term follow-up, three additional PAH cases were diagnosed, yielding a PAH incidence of 2.3%/year. All detected cases have remained at low risk status on oral PAH therapy at last follow-up. Conclusion: In adult BMPR2 mutation carriers, a multimodal screening program with regular follow-up allows early detection of PAH.
Published: 2020

31. Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation

Author: Caroline Ovaert, Damien Bonnet, Gérald Simonneau, Céline Chabanne, Pierre Thoré, Olivier Sitbon, Marc Humbert, Marilyne Lévy, Claire Dauphin, Florent Soubrier, Laurent Savale, E. Boiffard, Xavier Jaïs, Martine Remy-Jardin, Amélie Servettaz, Barbara Girerd, Anne Guillaumot, Ari Chaouat, Frédéric Perros, Maria-Rosa Ghigna, David Montani, Vincent Cottin, Mélanie Eyries, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Service d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de génétique [CHU Pitié-Salpêtrière], Service de cardiologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Clermont-Ferrand, CHU Pontchaillou [Rennes], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Hemodynamics, medicine.disease_cause, Gastroenterology, Vascular remodelling in the embryo, 03 medical and health sciences, 0302 clinical medicine, Diffusing capacity, Internal medicine, Parenchyma, medicine, Lung transplantation, Mutation, business.industry, Phenotype, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Vascular resistance, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2–41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.
Published: 2020

32. Familial pulmonary arterial hypertension by KDR heterozygous loss of function

Author: David Montani, Barbara Girerd, Frédéric Perros, Mélanie Eyries, Marc Humbert, Grégoire Manaud, Florent Soubrier, Nicholas W. Morrell, Marianne Riou, Nicolas Favrolt, Laurence Faivre, Stefan Gräf, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pneumologie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Pneumologie Soins Intensifs, Appareillage Respiratoire [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre chirurgical Marie Lannelongue, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), University of Cambridge [UK] (CAM), Addenbrooke's Hospital, Cambridge University NHS Trust, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Chirurgical Marie Lannelongue (CCML), and Perros, Frédéric
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Mutation, business.industry, Interstitial lung disease, medicine.disease, medicine.disease_cause, Major gene, 3. Good health, BMPR2, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030228 respiratory system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diffusing capacity, Immunology, Medicine, business, Gene, Loss function, Genetic association
Abstract: Beyond the major gene BMPR2, several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study.We prospectively analysed the KDR gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin (DLCOc) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low DLCOc, or have only decreased DLCOc, whereas non-carrier relatives have normal DLCOc. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal DLCOc.We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low DLCOc and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.
Published: 2020

33. Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

Author: Christopher J. Rhodes, Allan Lawrie, Robert V. MacKenzie Ross, Mark Toshner, Mélanie Eyries, Werner Seeger, Richard M. Salmon, Stefano Ghio, Laura Scelsi, Stephen J. Wort, Gabor Kovacs, Florent Soubrier, J. Simon R. Gibbs, Richard C. Trembath, Jennifer M. Martin, Nicholas W. Morrell, Matthias Haimel, Gerry Coghlan, Marc Humbert, Jay Suntharalingam, Charaka Hadinnapola, Cesare Danesino, Willem H. Ouwehand, Louise C. Daugherty, Carmen M. Treacy, David G. Kiely, Andrea Olschewski, Joanna Pepke-Zaba, Deborah Whitehorn, Anton Vonk Noordegraaf, Andrew J. Peacock, Robin Condliffe, Horst Olschewski, Paul A. Corris, Joshua Hodgson, Hossein Ardeschir Ghofrani, Arjan C. Houweling, Colin Church, Jingxu Guo, Stefan Gräf, Barbara Girerd, Katherine Yates, Harm Jan Bogaard, Ivana Nikolic, Luke S. Howard, Henning Gall, Laura Southgate, Olga Shamardina, Emilia M. Swietlik, Marta Bleda, Rajiv D. Machado, Inga Prokopenko, John Wharton, James Liley, Simon Holden, Paul B. Yu, Martin R. Wilkins, Shahin Moledina, David Montani, Paul D. Upton, Wei Li, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Swietlik, Emilia [0000-0002-4095-8489], Guo, Jingxu [0000-0002-1568-4842], Shamardina, Olga [0000-0003-4994-2157], Ouwehand, Willem [0000-0002-7744-1790], Toshner, Mark [0000-0002-3969-6143], Li, Wei [0000-0002-1924-3120], Graf, Stefan [0000-0002-1315-8873], Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, and British Heart Foundation
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Heterozygote, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Respiratory System, Mutation, Missense, GDF2, Critical Care and Intensive Care Medicine, Bone morphogenetic protein, BMP9, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Critical Care Medicine, Sex factors, Internal medicine, General & Internal Medicine, pulmonary arterial hypertension, medicine, Growth Differentiation Factor 2, Humans, In patient, 030212 general & internal medicine, Respiratory system, 11 Medical and Health Sciences, Science & Technology, business.industry, Case-control study, Heterozygote advantage, Middle Aged, 3. Good health, Transport protein, BMP10, Protein Transport, Endocrinology, 030228 respiratory system, Case-Control Studies, Bone Morphogenetic Proteins, Female, business, Life Sciences & Biomedicine
Abstract: International audience; Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
Published: 2020

34. Phenotype and outcome of PAH patients carrying a TBX4 mutation

Author: Pierre Thoré, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria Rosa Ghigna, Mélanie Eyries, Marilyne Levy, Caroline Ovaert, Amélie Servettaz, Anne Guillaumot, Claire Dauphin, Céline Chabanne, Emmanuel Boiffard, Vincent Cottin, Frédéric Perros, Gérald Simonneau, Sitbon Olivier, Florent Soubrier, Damien Bonnet, Martine Remy Jardin, Ari Chaouat, Marc Humbert, David Montani, Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hypertension artérielle pulmonaire : physiopathologie et innovation thérapeutique [Le Kremlin-Bicêtre], Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Médecine Interne, Immunologie clinique et maladies infectieuses [CHU Reims], Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], Service de Cardiologie [La Roche-sur-Yon], Centre Hospitalier Départemental site de la Roche-sur-Yon (CHD de la Roche-sur-Yon), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de pneumologie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Perros, Frédéric, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Marie-Lannelongue, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Gabriel Montpied (CHU), Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and AP-HP - Hôpital Antoine Béclère [Clamart]
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; INTRODUCTION:TBX4 mutation cause small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.METHODS:We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French PH Network.RESULTS:Twenty patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 (0-76) year-old and a female to male ratio of 3. Most of the patients were in NYHA functional class III or IV (70%) with a severe hemodynamic impairment (median pulmonary vascular resistance of 13.6 [6.2-41.8] Wood Units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity for carbon monoxide was decreased in all patients. High-resolution computed tomography showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients died and two underwent lung transplantation. One-, three- and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic PAH, and accumulation of cholesterol crystals within the lung parenchyma.CONCLUSION:PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.
Published: 2020

35. Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors

Author: Mostafa El Hajjam, Florent Soubrier, Augustin Ozanne, Gilles Lesur, Alain Beauchet, Philippe Charron, Pascal Lacombe, Aurélien Palmyre, Isabelle Bourgault-Villada, Jerome Lucas, Jérome Lesniak, Axel Dallongeville, Carole Fagnou, J. Sellier, Carma Karam, S. Binsse, Thierry Chinet, Mélanie Eyries, Sandra Blivet, Agnès Nicod-Tran, Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Epidemiology, Physiology, Maternal Health, Blood Pressure, Disease, Cardiovascular Medicine, Splenic artery, Vascular Medicine, Gastroenterology, Diagnostic Radiology, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Risk Factors, Pregnancy, Blood Flow, hemic and lymphatic diseases, Prevalence, Medicine and Health Sciences, Telangiectasia, Tomography, Multidisciplinary, Radiology and Imaging, Obstetrics and Gynecology, Arteries, Middle Aged, Prognosis, Body Fluids, 3. Good health, Blood, Cardiovascular Diseases, Hypertension, Medicine, Female, Telangiectasia, Hereditary Hemorrhagic, France, Anatomy, medicine.symptom, Aneurysms, Research Article, Adult, medicine.medical_specialty, Imaging Techniques, Science, Neuroimaging, Research and Analysis Methods, 03 medical and health sciences, Hypertensive Disorders in Pregnancy, Diagnostic Medicine, Internal medicine, medicine.artery, Multidetector Computed Tomography, medicine, Humans, Vascular Diseases, Aged, Retrospective Studies, Fetus, Aorta, business.industry, Case-control study, Biology and Life Sciences, Retrospective cohort study, Blood flow, Aneurysm, Computed Axial Tomography, 030104 developmental biology, Case-Control Studies, Medical Risk Factors, Cardiovascular Anatomy, Blood Vessels, Women's Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Splenic Artery, Follow-Up Studies, Neuroscience
Abstract: International audience; Background: Splenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT.Methods: We analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement.Results: SAA concerned 24.7% of HHT patients and 5.4% of controls, p
Published: 2020

36. Phenotype and outcome of pulmonary arterial hypertension patients carrying a

Author: Pierre, Thoré, Barbara, Girerd, Xavier, Jaïs, Laurent, Savale, Maria-Rosa, Ghigna, Mélanie, Eyries, Marilyne, Levy, Caroline, Ovaert, Amélie, Servettaz, Anne, Guillaumot, Claire, Dauphin, Céline, Chabanne, Emmanuel, Boiffard, Vincent, Cottin, Frédéric, Perros, Gérald, Simonneau, Olivier, Sitbon, Florent, Soubrier, Damien, Bonnet, Martine, Remy-Jardin, Ari, Chaouat, Marc, Humbert, and David, Montani
Subjects: Adult, Male, Bone Diseases, Developmental, Pulmonary Arterial Hypertension, Hip, Adolescent, Infant, Newborn, Infant, Patella, Middle Aged, Survival Rate, Young Adult, Phenotype, Ischium, Child, Preschool, Mutation, Humans, Female, Vascular Resistance, France, Child, T-Box Domain Proteins, Aged, Lung Transplantation, Retrospective Studies
Abstract: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (PAH due to
Published: 2019

37. Familial pulmonary arterial hypertension by

Author: Mélanie, Eyries, David, Montani, Barbara, Girerd, Nicolas, Favrolt, Marianne, Riou, Laurence, Faivre, Grégoire, Manaud, Frédéric, Perros, Stefan, Gräf, Nicholas W, Morrell, Marc, Humbert, and Florent, Soubrier
Subjects: Mutation, Humans, Familial Primary Pulmonary Hypertension, Genetic Predisposition to Disease, Vascular Endothelial Growth Factor Receptor-2, Genetic Association Studies
Abstract: Beyond the major gene
Published: 2019

38. Clinical and genetic findings in children with central nervous system arteriovenous fistulas

Author: Florent Soubrier, Guillaume Saliou, Marie-Christine Waill, Mélanie Eyries, Marta Iacobucci, Florence Coulet, Augustin Ozanne, and Jean-François Knebel
Subjects: Intracranial Arteriovenous Malformations, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Arteriovenous fistula, Gene mutation, Cohort Studies, Hemangioma, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Modified Rankin Scale, Internal medicine, medicine, Humans, Genetic Testing, Preschool, Child, Genetic testing, medicine.diagnostic_test, business.industry, Infant, Arteriovenous malformation, medicine.disease, Arteriovenous Fistula, Child, Preschool, Female, Mutation, Spinal Cord, 030104 developmental biology, Neurology, Heart failure, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE To assess the spectrum of genetic anomalies in a cohort of children presenting at least one cerebral or spinal pial arteriovenous fistula (AVF), and to describe their clinical characteristics. METHODS From 1988 to 2016, all consecutive patients with at least one cerebral or spinal pial AVF were screened for genetic disease. All patients aged
Published: 2017

39. Architecture génétique de l’hypertension pulmonaire : des gènes aux médicaments

Author: David Montani, Florence Coulet, Mélanie Eyries, Marc Humbert, Florent Soubrier, and Barbara Girerd
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, General Medicine
Abstract: RESUME La decouverte de nouveaux genes de susceptibilite a l’hypertension pulmonaire a bouleverse nos connaissances sur la physiopathologie de la maladie. A cote des mutations du gene BMPR2 qui sont, par leurs frequences et leurs effets, les principales mutations responsables des formes heritables de l’hypertension arterielle pulmonaire (HTAP) isolee, des mutations ont ete decrites dans le gene KCNK3 (TASK1) codant pour un canal potassium, le gene SMAD8 codant, comme BMPR2, pour une molecule de signalisation de la voie BMP, le gene CAV1 codant pour la caveoline-1. Les mutations des genes de l’endogline et du recepteur ACVRL1 s’inscrivent dans le cadre de la maladie de Rendu-Osler et la survenue de l’HTAP en aggrave la severite, et les mutations du gene TBX4 sont egalement responsables de formes syndromiques d’HTAP compliquant de facon rare le Small Patella Syndrome. Les mutations du gene EIF2AK4 (GCN2) sont responsables d’une forme rare et severe d’hypertension pulmonaire, la maladie veino-occlusive pulmonaire appelee aussi hemangiomatose capillaire pulmonaire. L’analyse des mecanismes d’action et de regulation de ces genes et des consequences fonctionnelles des mutations conduit a la conception de nouveaux traitements a visee etiologique de l’hypertension pulmonaire.
Published: 2017

40. Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers

Author: Jean-Yves Rioux, Virginie Escabasse, Hubert Ducou Le Pointe, Suzanne Verlhac, Ralph Epaud, Florent Soubrier, Isabelle Hau, Manuela Vasile, Stéphanie Franchi-Abella, Nurcan Soysal, Marie-France Carette, Natascha Remus, Sarah Robert, Aline Tamalet, Céline Delestrain, and Mélanie Eyries
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, High-resolution computed tomography, medicine.diagnostic_test, business.industry, Mucocutaneous zone, Genetic disorder, Arteriovenous malformation, ACVRL1, Endoglin, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Dysplasia, hemic and lymphatic diseases, Pediatrics, Perinatology and Child Health, otorhinolaryngologic diseases, medicine, medicine.symptom, Telangiectasia, business, 030217 neurology & neurosurgery
Abstract: SummaryBackground Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM). Aim to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT). Methods parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast. Results between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy. Conclusion This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642–649. © 2017 Wiley Periodicals, Inc.
Published: 2017

41. Characterization of

Author: Joshua, Hodgson, Emilia M, Swietlik, Richard M, Salmon, Charaka, Hadinnapola, Ivana, Nikolic, John, Wharton, Jingxu, Guo, James, Liley, Matthias, Haimel, Marta, Bleda, Laura, Southgate, Rajiv D, Machado, Jennifer M, Martin, Carmen M, Treacy, Katherine, Yates, Louise C, Daugherty, Olga, Shamardina, Deborah, Whitehorn, Simon, Holden, Harm J, Bogaard, Colin, Church, Gerry, Coghlan, Robin, Condliffe, Paul A, Corris, Cesare, Danesino, Mélanie, Eyries, Henning, Gall, Stefano, Ghio, Hossein-Ardeschir, Ghofrani, J Simon R, Gibbs, Barbara, Girerd, Arjan C, Houweling, Luke, Howard, Marc, Humbert, David G, Kiely, Gabor, Kovacs, Allan, Lawrie, Robert V, MacKenzie Ross, Shahin, Moledina, David, Montani, Andrea, Olschewski, Horst, Olschewski, Willem H, Ouwehand, Andrew J, Peacock, Joanna, Pepke-Zaba, Inga, Prokopenko, Christopher J, Rhodes, Laura, Scelsi, Werner, Seeger, Florent, Soubrier, Jay, Suntharalingam, Mark R, Toshner, Richard C, Trembath, Anton, Vonk Noordegraaf, Stephen J, Wort, Martin R, Wilkins, Paul B, Yu, Wei, Li, Stefan, Gräf, Paul D, Upton, and Nicholas W, Morrell
Subjects: Adult, Male, Heterozygote, Pulmonary Arterial Hypertension, DNA Copy Number Variations, Mutation, Missense, Original Articles, Middle Aged, Protein Transport, Sex Factors, Case-Control Studies, Bone Morphogenetic Proteins, Growth Differentiation Factor 2, Humans, Female
Abstract: Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260). Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
Published: 2019

42. Soft tissue angiomatosis: another PIK3CA ‐related disorder

Author: Louise Galmiche-Rolland, Sonia Ariche-Maman, Stéphanie Pannier, Florence Coulet, Sylvie Fraitag, Mélanie Eyries, Olivia Boccara, Florence Pedeutour, Thierry Jo Molina, Bérengère Dadone-Montaudié, Véronique Soupre, Service de dermatologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de radiologie pédiatrique [CHU Necker], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de chirurgie orthopédique et traumatologie pédiatrique [CHU Necker ], Service de chirurgie plastique et maxillofaciale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Service de génétique [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, 0301 basic medicine, Angiomatosis, Pathology, medicine.medical_specialty, Histology, Adolescent, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], Context (language use), PIK3CA-related overgrowth syndrome, Pathology and Forensic Medicine, Vascular anomaly, soft tissue angiomatosis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, PTEN, Hamartoma, Medical history, Family history, Child, Retrospective Studies, PTEN hamartoma of soft tissue, Leg, biology, business.industry, PTEN Phosphohydrolase, Macrocephaly, Infant, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Arm, biology.protein, Female, PTEN hamartoma tumor syndrome, medicine.symptom, Hamartoma Syndrome, Multiple, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; AIM:Angiomatosis of soft tissue (AST) is a, rare, high-flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumor syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft tissue. Given that AST is observed in patients with no history of PHTS, we hypothesized that non-syndromic AST arises as a consequence of a somatic mutation.METHODS AND RESULTS:Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients' personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed, and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio -0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups.CONCLUSIONS:AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.
Published: 2019

43. Widening the landscape of heritable pulmonary hypertension mutations in pediatric and adult cases

Author: David Montani, Vincent Cottin, Marc Humbert, Martine Reynaud-Gaubert, Claire Dromer, Florence Coulet, Céline Sanfiorenzo, Mélanie Eyries, Florent Soubrier, Barbara Girerd, Ari Chaouat, Marilyne Lévy, Grégoire Prévot, Romain Trésorier, Karine Nguyen, Damien Bonnet, Ali Houeijeh, Arnaud Bourdin, Sophie Nadaud, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre chirurgical Marie Lannelongue, Université Paris-Saclay, Centre National de Référence de l'Hypertension Artérielle Pulmonaire (UPRES - EA2705), Université Paris-Sud - Paris 11 (UP11), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Faculté des Sciences et Technologies [Université de Lorraine] (FST ), Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Hôpital Pasteur [Nice] (CHU), Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Centre Chirurgical Marie Lannelongue (CCML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MORNET, Dominique
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Adolescent, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Protein Receptors, Type II, medicine.disease_cause, Genetic analysis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Growth Differentiation Factor 2, polycyclic compounds, Humans, Medicine, Familial Primary Pulmonary Hypertension, Hemangioma, Capillary, 030212 general & internal medicine, Young adult, Child, Gene, Aged, Aged, 80 and over, Mutation, Lung, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, Middle Aged, medicine.disease, Pulmonary hypertension, 3. Good health, BMPR2, medicine.anatomical_structure, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Proteins, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Pulmonary Veno-Occlusive Disease, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, T-Box Domain Proteins, business
Abstract: International audience; Background Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known.Methods We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases).Results Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients.Conclusion Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.
Published: 2019

44. Clinical implications of CTNNA1 germline mutations in asymptomatic carriers

Author: Yann Parc, Isabelle Coupier, Erell Guillerm, Jerôme Bellanger, Aurélie Maran Gonzalez, Magali Svrcek, Jeanne Netter, Jérôme Alexandre Denis, Chrystelle Colas, Mathilde Warcoin, A. Mourregot, Mohamed Zizi, Florent Soubrier, Florence Coulet, Axelle Canard, Mélanie Eyries, Hélène Delhomelle, Véronica Cusin, Patrick R. Benusiglio, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Curie [Paris], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Sorbonne Université (SU), Institut du Cancer de Montpellier (ICM), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], CHU Montpellier, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Male, Cancer Research, medicine.medical_treatment, medicine.disease_cause, Gastroenterology, Germline, 0302 clinical medicine, Surgical oncology, Mutation, General Medicine, Middle Aged, Prognosis, 3. Good health, Pedigree, Oncology, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Hereditary diffuse gastric cancer, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Germline mutation, Gastrectomy, Stomach Neoplasms, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Retrospective Studies, Diffuse gastric cancer, CDH1, business.industry, Signet-ring cell, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Hereditary cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Asymptomatic Diseases, CTNNA1, business, Asymptomatic carrier, Carcinoma, Signet Ring Cell, alpha Catenin, Follow-Up Studies
Abstract: International audience; In 2017, we implemented CTNNA1 germline analysis in probands suspected of having hereditary diffuse gastric cancer. Here, we report the results from a retrospective series of 41 cases, including the identification of a new family with a CTNNA1 mutation and the first prophylactic total gastrectomy in an asymptomatic carrier after a normal upper endoscopy. Diffuse gastric cancer foci with loss of catenin alpha-1 expression were seen in the resected tissue, suggesting that CTNNA1 and CDH1 germline mutations behave in a similar manner. Life-changing prophylactic total gastrectomy should therefore also be considered in CTNNA1 mutation carriers.
Published: 2019

45. Genetic counselling in a national referral centre for pulmonary hypertension

Author: Mélanie Eyries, Laurent Godinas, David Montani, Yuichi Tamura, Laurent Savale, Olivier Sitbon, Marc Humbert, Edmund M.T. Lau, Florence Coulet, Florent Soubrier, Barbara Girerd, Xavier Jaïs, Gérald Simonneau, Florence Parent, Azzedine Yaici, and Benjamin Sztrymf
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Activin Receptors, Type II, Hypertension, Pulmonary, Genetic counseling, Caveolin 1, Genetic Counseling, Nerve Tissue Proteins, Receptors, Cell Surface, Disease, Protein Serine-Threonine Kinases, 030204 cardiovascular system & hematology, Bone Morphogenetic Protein Receptors, Type II, Asymptomatic, Tertiary Care Centers, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Antigens, CD, medicine, Humans, Familial Primary Pulmonary Hypertension, Family, Genetic Testing, Family history, Preimplantation Diagnosis, Asymptomatic Diseases, business.industry, Endoglin, ACVRL1, medicine.disease, Pulmonary hypertension, BMPR2, 030228 respiratory system, Smad8 Protein, Mutation, Pulmonary Veno-Occlusive Disease, Female, France, medicine.symptom, business
Abstract: Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling.Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension.Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres.
Published: 2015

46. Loss of Function ABCC8 Mutations in Pulmonary Arterial Hypertension

Author: Michael S. Bohnen, Charaka Hadinnapola, Joanna Pepke-Zaba, Anton Vonk Noordegraaf, David G. Kiely, Stephen J. Wort, Andrew J. Peacock, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Erika B. Rosenzweig, Frederick E. Dewey, Wendy K. Chung, Kevin J. Sampson, Mélanie Eyries, Paul A. Corris, Robert S. Kass, Lijiang Ma, Allan Lawrie, Yufeng Shen, Colin G. Nichols, Mark Toshner, Katherine Yates, Jeffrey G. Reid, Christophe Guignabert, Matthias Haimel, J. Simon R. Gibbs, Gerry Coghlan, Marc Humbert, John D. Overton, Harm Jan Bogaard, Arjan C. Houweling, Colin Church, Jennifer M. Martin, Robert V. MacKenzie Ross, Stefan Gräf, Barbara Girerd, Martin R. Wilkins, John Wharton, David Montani, Na Zhu, Marta Bleda, Aris Baras, Florent Soubrier, Conor McClenaghan, Nicholas W. Morrell, Usha Krishnan, Hongjian Qi, Jay Suntharalingam, Richard C. Trembath, Carmen M. Treacy, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and APH - Quality of Care
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, DNA Mutational Analysis, Mutation, Missense, 030204 cardiovascular system & hematology, Sulfonylurea Receptors, ABCC8, Article, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, Internal medicine, medicine, Humans, Exome, Familial Primary Pulmonary Hypertension, Child, Pathological, Loss function, biology, business.industry, General Medicine, medicine.disease, Pulmonary hypertension, 030104 developmental biology, medicine.anatomical_structure, Amino Acid Substitution, Pulmonary artery, biology.protein, Vascular resistance, Cardiology, Female, business
Abstract: Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3 , was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Published: 2018

47. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018

48. Characteristics of Pulmonary Arterial Hypertension in Affected Carriers of a Mutation Located in the Cytoplasmic Tail of Bone Morphogenetic Protein Receptor Type 2

Author: Gérald Simonneau, Barbara Girerd, Anton Vonk-Noordegraaf, Laurent Savale, David Montani, Olivier Sitbon, Frances S. de Man, Arjan C. Houweling, Marc Humbert, Florence Coulet, Mélanie Eyries, Cathelijne E. E. van der Bruggen, Xavier Jaïs, Peter Dorfmüller, Florent Soubrier, Pulmonary medicine, Human genetics, and ICaR - Heartfailure and pulmonary arterial hypertension
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Heterozygote, medicine.medical_specialty, Hypertension, Pulmonary, Population, Bone Morphogenetic Protein Receptors, Type II, Critical Care and Intensive Care Medicine, medicine.disease_cause, Bone morphogenetic protein, Cohort Studies, Internal medicine, medicine, Humans, education, Mutation, education.field_of_study, business.industry, Calcium channel, Point mutation, BMPR2, Endocrinology, Female, Signal transduction, Cardiology and Cardiovascular Medicine, business, ACVR2A
Abstract: BACKGROUND Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling. METHODS This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain. RESULTS We identified 171 carriers affected with PAH with a mutated BMPR2 . Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 ± 12.1 years and 35.7 ± 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 ± 3.5 and 17.4 ± 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain. CONCLUSIONS Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.
Published: 2015

49. Identification of novel rare sequence variation underlying heritable pulmonary arterial hypertension

Author: Laura Southgate, Barbara Girerd, Andrew J. Peacock, Olga Shamardina, David G. Kiely, Marta Bleda, Mark Toshner, Robin Condliffe, Marc Humbert, Werner Seeger, Stefano Ghio, Arjan C. Houweling, Colin Church, Dan F. Stein, Katherine Yates, Matthias Haimel, Stephen J. Wort, Stefan Gräf, David Montani, Christopher J. Rhodes, Hossein Ardeschir Ghofrani, Willem H. Ouwehand, Allan Lawrie, John Wharton, Shahin Moledina, Carmen M. Treacy, Joanna Pepke-Zaba, Richard M. Salmon, Emilia M. Swietlik, Richard C. Trembath, Anton Vonk Noordegraaf, Bin Liu, Harm Jan Bogaard, Michael Newnham, Henning Gall, Gerry Coghlan, David A. van Heel, Robert V. MacKenzie Ross, Nicole Soranzo, Gabor G. Kovacs, Horst Olschewski, Inga Prokopenko, Florent Soubrier, Martin R. Wilkins, Nicholas W. Morrell, Jay Suntharalingam, Rajiv D. Machado, Mélanie Eyries, Andrea Olschewski, Mark Southwood, Micheala A. Aldred, Simon Holden, Joshua Hodgson, Laura Scelsi, Quentin Waisfisz, Wei Li, Luke Howard, Charaka Hadinnapola, Cesare Danesino, Louise C. Daugherty, Deborah Whitehorn, Paul A. Corris, Paul D. Upton, J. Simon R. Gibbs, and Jennifer M. Martin
Subjects: Genetics, Whole genome sequencing, 0303 health sciences, GDF2, 030204 cardiovascular system & hematology, Biology, Bone morphogenetic protein, 3. Good health, BMPR2, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Genetic variation, Gene, 030304 developmental biology, Transforming growth factor
Abstract: Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
Published: 2017
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50. Prenatal molecular diagnosis in RASA1-related disease

Author: Philippe Charron, Stéphanie Staraci, Mélanie Eyries, Pascal Lacombe, Philippe Dufour, Florent Soubrier, Marie-Victoire Senat, Augustin Ozanne, Thierry Chinet, and Aurélien Palmyre
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Pediatrics, Context (language use), Prenatal diagnosis, Disease, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, medicine, Humans, Genetic Testing, Brain abscess, Stroke, Genetics (clinical), Genetic testing, medicine.diagnostic_test, business.industry, Obstetrics and Gynecology, Autosomal dominant trait, p120 GTPase Activating Protein, medicine.disease, Penetrance, Surgery, 030104 developmental biology, Female, business, 030217 neurology & neurosurgery
Abstract: RASA1-related disease is a rare autosomal dominant disease characterized by capillary malformations, arteriovenous malformations (AVMs), and/or arteriovenous fistulas (AFVs). Penetrance is nearly complete and vascular malformations may cause serious complications such as organ injury due to oxygenation disorder, brain abscess, hemorrhage, and stroke. Early diagnosis is useful in order to discuss optimal management, including AVMs/AVFs embolization or surgical procedures, and try to prevent some of the complications. In this context, molecular testing of RASA1 gene mutation in relatives may help to better manage the family. All arteriovenous malformations are however not accessible to such procedures. In addition, these therapeutic procedures may result in potential side effects and complications. A couple was referred to our genetics unit and asked us for prenatal genetic testing about a RASA1 mutation. Here, we discuss about arguments that led our team to accept prenatal testing. To the best of our knowledge, no molecular prenatal diagnosis was reported until now in RASA1-related diseases. This first report of prenatal diagnosis in RASA1-related diseases may also offer perspectives for a more general discussion in the field of inherited arteriovenous malformations.
Published: 2017

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