Taisuke Ishikawa1, Hiroyuki Mishima2, Julien Barc3, Masanori P Takahashi4, Keiichi Hirono5, Shigenori Terada6, Shinya Kowase7, Teruki Sato8, Yasushi Mukai9, Yoshiaki Yui10, Kimie Ohkubo11, Hiroki Kimoto12, Hiroyuki Watanabe8, Yukiko Hata13, Takeshi Aiba14, Seiko Ohno15, Akiko Chishaki16, Wataru Shimizu17, Minoru Horie18, Fukiko Ichida5, Akihiko Nogami10, Koh-Ichiro Yoshiura2, Jean-Jacques Schott3, Naomasa Makita1. 1. Omics Research Center (T.I., N.M.), National Cerebral and Cardiovascular Center, Suita, Japan. 2. Department of Human Genetics (H.M., K.-I.Y.), Nagasaki University Graduate School of Biomedical Sciences, Japan. 3. L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, France (J.B., J.-J.S.). 4. Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan (M.P.T.). 5. Department of Pediatrics, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Japan (K.H., F.I.). 6. Department of Cardiovascular Medicine, Shin-Oyama City Hospital, Japan (S.T.). 7. Division of Cardiology, Yokohama Rosai Hospital, Japan (S.K.). 8. Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, Japan (T.S., H.W.). 9. Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (Y.M.). 10. Department of Cardiology, Faculty of Medicine, Tsukuba University, Japan (Y.Y., A.N.). 11. Department of Cardiovascular Medicine, Nihon University School of Medicine, Tokyo, Japan (K.O.). 12. Department of Molecular Physiology (H.K.), Nagasaki University Graduate School of Biomedical Sciences, Japan. 13. Department of Legal Medicine, Graduate School of Medicine, University of Toyama, Japan (Y.H.). 14. Department of Cardiovascular Medicine (T.A.), National Cerebral and Cardiovascular Center, Suita, Japan. 15. Department of Bioscience and Genetics (S.O.), National Cerebral and Cardiovascular Center, Suita, Japan. 16. Clinical Nursing Laboratory, School of Medicine, Kyushu University, Fukuoka, Japan (A.C.). 17. Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). 18. Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Ohtsu, Japan (M.H.).
Abstract
BACKGROUND: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. METHODS: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). RESULTS: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. CONCLUSIONS: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.
BACKGROUND: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. METHODS: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). RESULTS: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. CONCLUSIONS:Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486