title: A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation.
abstract: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF.
  
  
  
  We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death.
  
  
  
  Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland daniel.gudbjartsson@decode.is davidar@landspitali.is.|School of Engineering and Natural Sciences, University of Iceland, Hjardarhaga 4, 107 Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.|Department of Medicine, Landspitali- The National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Asmundur
authors.initials: A
authors.lastname: Oddsson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Olafur Th
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Jona
authors.initials: J
authors.lastname: Saemundsdottir
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Hafdis Th
authors.initials: HT
authors.lastname: Helgadottir
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Hrefna
authors.initials: H
authors.lastname: Johannsdottir
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: Institute of Community Medicine, University of Tromsø, Postboks 6050, Langnes, 9037 Tromsø, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.affiliation: Institute of Community Medicine, University of Tromsø, Postboks 6050, Langnes, 9037 Tromsø, Norway.|Department of Cardiology, University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway.
authors.forename: Maja-Lisa
authors.initials: ML
authors.lastname: Løchen
authors.affiliation: School of Pharmacy, Chinese University of Hong Kong, Hong Kong.
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
authors.affiliation: Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, 30 Ngan Shing Street, Sha Tin 999077 Hong Kong.
authors.forename: Ronald C W
authors.initials: RC
authors.lastname: Ma
authors.affiliation: Children's Hospital, Landspitali- The National University Hospital, Hringbraut 101 Reykjavik, Iceland.
authors.forename: Gunnlaugur
authors.initials: G
authors.lastname: Sigfusson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Hjardarhaga 4, 107 Reykjavik, Iceland.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: Department of Medicine, Landspitali- The National University Hospital, Hringbraut, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
authors.forename: Guðmundur
authors.initials: G
authors.lastname: Thorgeirsson
authors.affiliation: Department of Internal Medicine, Akureyri Hospital, Eyrarlandsvegur, 600 Akureyri, Iceland.
authors.forename: Jon Th
authors.initials: JT
authors.lastname: Sverrisson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland daniel.gudbjartsson@decode.is davidar@landspitali.is.|Department of Medicine, Landspitali- The National University Hospital, Hringbraut, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
authors.forename: David O
authors.initials: DO
authors.lastname: Arnar
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000208:ethnology / Q000209:etiology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D017353:Gene Deletion; D005808:Genes, Recessive / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007055:Iceland / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D018994:Myosin Light Chains / Q000235:genetics*; D010375:Pedigree; D012307:Risk Factors; D012518:Sarcomeres; D016415:Sequence Alignment / Q000379:methods; D012804:Sick Sinus Syndrome / Q000208:ethnology / Q000235:genetics; D020521:Stroke / Q000208:ethnology / Q000235:genetics
chemical_list: C000599129:MYL4 protein, human; D018994:Myosin Light Chains
keywords: Atrial fibrillation; Early onset; Genetics; Sarcomere