Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

• DOI: 10.1161/circulationaha.117.028351
• Publication Date: 2017-10-03T00:40:22Z
• Authors: Charaka Hadinnapola; Marta Bleda; Matthias Haimel; Nicholas Screaton; Andrew Swift; Peter Dorfmüller; Stephen D. Preston; Mark Southwood; Jules Hernandez-S...; Jennifer Martin; Carmen Treacy; Katherine Yates; Harm Bogaard; Colin Church; Gerry Coghlan; Robin Condliffe; Paul A. Corris; Simon Gibbs; Barbara Girerd; Simon Holden; Marc Humbert; David G. Kiely; Allan Lawrie; Rajiv Machado; Robert MacKenzie ...; Shahin Moledina; David Montani; Michael Newnham; Andrew Peacock; Joanna Pepke-Zaba; Paula Rayner-Matt...; Olga Shamardina; Florent Soubrier; Laura Southgate; Jay Suntharalingam; Mark Toshner; Richard Trembath; Anton Vonk Noorde...; Martin R. Wilkins; Stephen J. Wort; John Wharton; ; Stefan Gräf; Nicholas W. Morrell; Timothy Aitman; David Bennett; Mark Caulfield; Patrick Chinnery; Daniel Gale; Ania Koziell; Taco W Kuijpers; Michael A Laffan; Eamonn Maher; Hugh S Markus; Willem H Ouwehand; David Perry; F Lucy Raymond; Irene Roberts; Kenneth Smith; Adrian Thrasher; Hugh Watkins; Catherine Williamson; Geoffrey Woods; Sofie Ashford; John R Bradley; Debra Fletcher; Tracey Hammerton; Roger James; Nathalie Kingston; Willem H Ouwehand; Christopher J Pen...; F Lucy Raymond; Kathleen Stirrups; Marijke Veltman; Tim Young; Sofie Ashford; Matthew Brown; Naomi Clements-Brod; John Davis; Eleanor Dewhurst; Marie Erwood; Amy Frary; Rachel Linger; Sofia Papadia; Karola Rehnstrom; Hannah Stark; David Allsup; Steve Austin; Tamam Bakchoul; Tadbir K Bariana; Paula Bolton-Maggs; Elizabeth Chalmers; Peter Collins; Wendy N Erber; Tamara Everington; Remi Favier; Kathleen Freson; Bruce Furie; Michael Gattens; Keith Gomez; Daniel Greene; Andreas Greinacher; Daniel Hart; Johan WM Heemskerk; Yvonne Henskens; Rashid Kazmi; David Keeling; Anne M Kelly; Michael A Laffan; Michele P Lambert; Claire Lentaigne; Ri Liesner; Sarah Mangles; Mary Mathias; Carolyn M Millar; Andrew Mumford; Paquita Nurden; Willem H Ouwehand; Sofia Papadia; Jeanette Payne; John Pasi; David J Perry; Kathelijne Peerlinck; Michael Richards; Matthew Rondina; Catherine Roughley; Sol Schulman; Harald Schulze; Marie Scully; Suthesh Sivapalar...; R Campbell Tait; Kate Talks; Jecko Thachil; Ernest Turro; Cheng-Hock Toh; Chris Van Geet; Minka De Vries; Timothy Q Warner; Sarah Westbury; Abigail Furnell; Rutendo Mapeta; Ilenia Simeoni; Simon Staines; Jonathan Stephens; Kathleen Stirrups; Deborah Whitehorn; Christopher Watt; Antony Attwood; Louise Daugherty; Sri VV Deevi; Csaba Halmagyi; Fengyuan Hu; Roger James; Vera Matser; Stuart Meacham; Karyn Megy; Christopher J Pen...; Kathleen Stirrups; Catherine Titterton; Salih Tuna; Ping Yu; Julie von Ziegenw...; William Astle; Keren Carss; Daniel Greene; Hana Lango-Allen; Ernest Turro; William Astle; Daniel Greene; Sylvia Richardson; Ernest Turro; Paul Calleja; Stuart Rankin; Wojciech Turek; Christine Bryson; Julie Anderson; Debra Fletcher; Coleen McJannet; Sophie Stock; Tim Young; Evangeline Wassmer; Aman Sohal; Saikat Santra; Julie Vogt; Manali Chitre; Deepa Krishnakumar; Gautum Ambegaonkar; Anna Maw; Ruth Armstrong; Soo-Mi Park; Sarju Mehta; Joan Paterson; Jenny Carmichael; Louise Allen; Anke Hensiek; Helen Firth; Penelope Stein; Patrick Deegan; Rainer Doffinger; Alasdair Parker; Maria Bitner-Glin...; Richard Scott; Jane Hurst; Elisabeth Rosser; Melissa Lees; Emma Clement; Robert Henderson; Dorothy Thompson; Alice Gardham; Paul Gissen; Dragana Josifova; Ellen Thomas; Chris Patch; Charu Deshpande; Frances Flinter; Muriel Holder; Natalie Canham; Emma Wakeling; Susan Holder; Neeti Ghali; Angie Brady; Virginia Clowes; Robert MacLaren; Andrew Webster; Anthony Moore; Gavin Arno; Michel Michaelides; Julia Rankin; Manju Kurian; Elaine Murphy; Keren Carss; Alba Sanchis-Juan; Marie Erwood; Eleanor Dewhurst; Detelina Grozeva; F Lucy Raymond; Evan Reid; Geoff Woods; Marc Tischkowitz; Richard Sandford; Sonia Ali; Amanda Creaser-Myers; Victoria Cookson; Rosa DaCosta; Natalie Dormand; Pavandeep K Ghata...; Alan Greenhalgh; Anna Huis in’t Veld; Fiona Kennedy; Rob Mackenzie Ross; Larahmie Masati; Sharon Meehan; Shokri Othman; Val Pollock; Gary Polwarth; Christopher J Rhodes; Kevin Rue-Albrecht; Gwen Schotte; Debbie Shipley; Yvonne Tan; Ivy Wanjiku; John Wort; Kenneth Smith; Taco Kuijpers; Adrian Thrasher; James Thaventhiran; Matthew Brown; Hana Lango Allen; Ilenia Simeoni; Emily Staples; Crina Samarghitean; 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; Rainer Doffinger; Elizabeth Drewe; David Edgar; William Egner; Rohit Ghurye; Kimberley Gilmour; Sarah Goddard; Pavel Gordins; Sofia Grigoriadou; Scott Hackett; Rosie Hague; Grant Hayman; Archana Herwadkar; Aarnoud Huissoon; Stephen Jolles; Peter Kelleher; Dinakantha Kumara...; 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; Ravishankar Sargur; Sinisa Savic; Suranjith Senevir...; Carrock Sewell; Hans Stauss; Moira Thomas; Steve Welch; Lisa Willcocks; Nigel Yeatman; Patrick Yong
• Keywords: Male; CAPILLARY HEMANGIOMATOSIS; Cardiac & Cardiovascular Systems; Heredity; DNA Mutational Analysis; NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH; Pulmonary/diagnosis; VENOOCCLUSIVE-DISEASE; Gene Frequency; Risk Factors; pulmonary hypertension; genetics; Prospective Studies; Tomography; 1102 Cardiorespiratory Medicine and Haematology; Middle Aged; Protein-Serine-Threonine Kinases; DIFFUSION CAPACITY; X-Ray Computed; Pedigree; 3. Good health; [SDV] Life Sciences [q-bio]; Europe; Phenotype; Type II/genetics; Hypertension; Female; Life Sciences & Biomedicine; pulmonary veno-occlusive disease; CT; Adult; genetics, human; hypertension; pulmonary; Protein-Serine-Threonine Kinases/genetics; Hypertension, Pulmonary; hypertension, pulmonary; 610; Pulmonary Artery; Bone Morphogenetic Protein Receptors, Type II; Type II; 1117 Public Health and Health Services; Young Adult; Predictive Value of Tests; Humans; Arterial Pressure; Genetic Predisposition to Disease; human; Genetic Association Studies; Retrospective Studies; Aged; Science & Technology; pulmonary venoocclusive disease; BMPR2; Pulmonary Artery/physiopathology; 1103 Clinical Sciences; Bone Morphogenetic Protein Receptors; EIF2AK4; Peripheral Vascular Disease; Cardiovascular System & Hematology; REGISTRY; Arterial Pressure/genetics; Mutation; Cardiovascular System & Cardiology; prognosis; mutation; Tomography, X-Ray Computed

Background:

Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.

Methods:

Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.

Results:

Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival.

Conclusions:

Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.