title: Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy.
abstract: BACKGROUND
  Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases.
  
  
  OBJECTIVE
  This study aimed to identify new genes involved in pediatric cardiomyopathy.
  
  
  METHODS
  The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies.
  
  
  RESULTS
  We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3, a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling.
  
  
  CONCLUSIONS
  Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors: Rowida
authors: R
authors: Almomani
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Judith M A
authors: JM
authors: Verhagen
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors: Johanna C
authors: JC
authors: Herkert
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Erwin
authors: E
authors: Brosens
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Karin Y
authors: KY
authors: van Spaendonck-Zwarts
authors: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Angeliki
authors: A
authors: Asimaki
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors: Paul A
authors: PA
authors: van der Zwaag
authors: Department of Pediatric Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Ingrid M E
authors: IM
authors: Frohn-Mulder
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Centogene AG, Rostock, Germany.
authors: Aida M
authors: AM
authors: Bertoli-Avella
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors: Ludolf G
authors: LG
authors: Boven
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Marjon A
authors: MA
authors: van Slegtenhorst
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Jasper J
authors: JJ
authors: van der Smagt
authors: Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Wilfred F J
authors: WF
authors: van IJcken
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
authors: Bert
authors: B
authors: Timmer
authors: University of Groningen, University Medical Center Groningen, Division of Neonatology, Beatrix Children's Hospital, Groningen, the Netherlands.
authors: Margriet
authors: M
authors: van Stuijvenberg
authors: Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Rob M
authors: RM
authors: Verdijk
authors: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Jeffrey E
authors: JE
authors: Saffitz
authors: Department of Pediatric Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Frederik A
authors: FA
authors: du Plessis
authors: Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Michelle
authors: M
authors: Michels
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Robert M W
authors: RM
authors: Hofstra
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors: Richard J
authors: RJ
authors: Sinke
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Durrer Center for Cardiogenetic Research, Utrecht, the Netherlands.
authors: J Peter
authors: JP
authors: van Tintelen
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Marja W
authors: MW
authors: Wessels
authors: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands. Electronic address: j.d.h.jongbloed@umcg.nl.
authors: Jan D H
authors: JD
authors: Jongbloed
authors: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Ingrid M B H
authors: IM
authors: van de Laar
mesh_terms: D017668:Age of Onset; D000818:Animals; D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D004452:Echocardiography / Q000379:methods; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology*; D011379:Prognosis
chemical_list: C437337:MIDORI protein, mouse; D009124:Muscle Proteins
keywords: exome sequencing; homozygous alpha-kinase 3 mutations; hypertrophy; intercalated disc