Alexandros Protonotarios1, Andreas Brodehl2, Angeliki Asimaki3, Joanna Jager4, Ellie Quinn5, Caroline Stanasiuk2, Sandra Ratnavadivel2, Marta Futema4, Mohammed M Akhtar6, Thomas D Gossios5, Michael Ashworth7, Konstantinos Savvatis8, Volker Walhorn9, Dario Anselmetti9, Perry M Elliott6, Petros Syrris4, Hendrik Milting2, Luis R Lopes6. 1. Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. Electronic address: alexandros.protonotarios.10@ucl.ac.uk. 2. Erich and Hanna Klessmann Institute for Cardiovascular Research & Development (EHKI), Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Germany. 3. Cardiology Clinical Academic Group, St George's University of London, Cranmer Terrace, London, United Kingdom. 4. Institute of Cardiovascular Science, University College London, London, United Kingdom. 5. Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom. 6. Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom. 7. Department of Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 8. Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. 9. Experimental Biophysics and Applied Nanoscience, Physics Department, Bielefeld Institute for Nanoscience (BINAS), Bielefeld University, Bielefeld, Germany.
Abstract
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity. METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing. RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates. CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity. METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing. RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates. CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.
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
Authors: Miriam Zink; Anne Seewald; Mareike Rohrbach; Andreas Brodehl; Daniel Liedtke; Tatjana Williams; Sarah J Childs; Brenda Gerull Journal: Int J Mol Sci Date: 2022-08-23 Impact factor: 6.208
Authors: Maen D Abou Ziki; Neha Bhat; Arpita Neogi; Tristan P Driscoll; Nelson Ugwu; Ya Liu; Emily Smith; Johny M Abboud; Salah Chouairi; Martin A Schwartz; Joseph G Akar; Arya Mani Journal: Hum Mutat Date: 2021-07-29 Impact factor: 4.700