title: Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene.
abstract: BACKGROUND
  Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin.
  
  
  RESULTS
  All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance.
  
  
  CONCLUSIONS
  In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. j.p.van.tintelen@medgen.umcg.nl
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Van Gelder
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Albert J H
authors.initials: AJ
authors.lastname: Suurmeijer
authors.forename: Ans C P
authors.initials: AC
authors.lastname: Wiesfeld
authors.forename: Jan D H
authors.initials: JD
authors.lastname: Jongbloed
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
authors.forename: Jan B M
authors.initials: JB
authors.lastname: Kuks
authors.forename: Karin Y
authors.initials: KY
authors.lastname: van Spaendonck-Zwarts
authors.forename: Nicolette
authors.initials: N
authors.lastname: Notermans
authors.forename: Ludolf
authors.initials: L
authors.lastname: Boven
authors.forename: Freek
authors.initials: F
authors.lastname: van den Heuvel
authors.forename: Hermine E
authors.initials: HE
authors.lastname: Veenstra-Knol
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
mesh_terms: D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D003893:Desmin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D003893:Desmin