title: A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation.
abstract: BACKGROUND
  Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins.
  
  
  RESULTS
  Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners.
  
  
  CONCLUSIONS
  Thus, our data conclude that, similar to previously described ANK2 loss-of-function "point mutations", large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed.
authors.affiliation: Department of Clinical Genetics, Austin Hospital, Melbourne, Vic, Australia; Department of Genetic Medicine, Royal Melbourne Hospital, Melbourne, Vic, Australia. Electronic address: aamira.huq@mh.org.au.
authors.forename: A J
authors.initials: AJ
authors.lastname: Huq
authors.affiliation: Victorian Clinical Genetics Services, Melbourne, Vic, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Pertile
authors.affiliation: Department of Cardiology, Royal Children's Hospital, Melbourne, Vic, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia; Murdoch Childrens Research Institute, Melbourne, Vic, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Davis
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute; Departments of Physiology & Cell Biology and Internal Medicine; Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: H
authors.initials: H
authors.lastname: Landon
authors.affiliation: Department of Genetic Medicine, Royal Melbourne Hospital, Melbourne, Vic, Australia; Department of Pathology, University of Melbourne, Melbourne, Vic, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: James
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute; Departments of Physiology & Cell Biology and Internal Medicine; Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: Department of Genetic Medicine, Royal Melbourne Hospital, Melbourne, Vic, Australia; Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Vohra
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute; Departments of Physiology & Cell Biology and Internal Medicine; Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Department of Clinical Genetics, Austin Hospital, Melbourne, Vic, Australia; Victorian Clinical Genetics Services, Melbourne, Vic, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia; Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Vic, Australia.
authors.forename: M B
authors.initials: MB
authors.lastname: Delatycki
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000503:physiopathology; D000328:Adult; D017487:Ankyrins / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005190:Family; D005260:Female; D005315:Fetal Diseases / Q000235:genetics / Q000503:physiopathology; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D011247:Pregnancy; D014178:Translocation, Genetic
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins
keywords: ANK2; Ankyrin-B; Ankyrin-B syndrome; Cardiac arrhythmia; Chromosome 4 translocation; Long QT syndrome type 4