title: Isolated X-linked hypertrophic cardiomyopathy caused by a novel mutation of the four-and-a-half LIM domain 1 gene.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction has been associated with marked exercise intolerance and poor prognosis. However, molecular pathogenesis of this phenotype remains unexplained in a large proportion of cases.
  
  
  RESULTS
  We performed whole exome sequencing as an initial genetic test in a large Czech family with 3 males affected by nonobstructive hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction in end-stage disease. A novel frameshift mutation of four-and-a-half LIM domain 1 gene (FHL1) (c.599_600insT; p.F200fs32X) was detected in these individuals. The mutation does not affect transcription, splicing, and stability of FHL1 mRNA and results in production of truncated FHL1 protein, which is contrary to heart tissue homogenate not detectable in frozen tissue sections of myocardial biopsy of affected males. The identified mutation cosegregated also with abnormal ECG and with 1 case of apical hypertrophic cardiomyopathy in heterozygous females. Although skeletal muscle involvement is a common finding in FHL1-related diseases, we could exclude myopathy in all mutation carriers.
  
  
  CONCLUSIONS
  We identified a novel FHL1 mutation causing isolated hypertrophic cardiomyopathy with X-chromosomal inheritance.
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannova
authors.forename: Milos
authors.initials: M
authors.lastname: Kubanek
authors.forename: Marek
authors.initials: M
authors.lastname: Sramko
authors.forename: Lenka
authors.initials: L
authors.lastname: Piherova
authors.forename: Lenka
authors.initials: L
authors.lastname: Noskova
authors.forename: Katerina
authors.initials: K
authors.lastname: Hodanova
authors.forename: Viktor
authors.initials: V
authors.lastname: Stranecky
authors.forename: Anna
authors.initials: A
authors.lastname: Pristoupilova
authors.forename: Jana
authors.initials: J
authors.lastname: Sovova
authors.forename: Tomas
authors.initials: T
authors.lastname: Marek
authors.forename: Jana
authors.initials: J
authors.lastname: Maluskova
authors.forename: Petr
authors.initials: P
authors.lastname: Ridzon
authors.forename: Josef
authors.initials: J
authors.lastname: Kautzner
authors.forename: Helena
authors.initials: H
authors.lastname: Hulkova
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins
keywords: cardiomyopathy, hypertrophic; exome; heart failure, diastolic