title: Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death.
abstract: BACKGROUND
  Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death.
  
  
  RESULTS
  An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased.
  
  
  CONCLUSIONS
  Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies.
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.). yxue618@gmail.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Aliz R
authors.initials: AR
authors.lastname: Rao
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Quadrelli
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Alicia
authors.initials: A
authors.lastname: Vaglio
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Verena
authors.initials: V
authors.lastname: Rupp
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Christine
authors.initials: C
authors.lastname: Beichler
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schapacher-Tilp
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: From the Emory Genetics Laboratory (Y.X.), Division of Medical Genetics (W.R.W.), Department of Human Genetics, Emory University, Atlanta, GA; Friedrich-Baur Institut, Neurologische Klinik, Klinikum der Universität, München, Germany (B.S.); Department of Human Genetics, UCLA School of Medicine, CA (A.R.R., S.F.N.); Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay (R.Q., A.V.); Institute of Human Genetics, Medical University of Graz (V.R., C.B., C.W.); and Department for Mathematics and Scientific Computing, Karl-Franzens-University Graz, Graz, Austria (G.S.-T.).
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics*; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000473:pathology*; D059472:Exome / Q000235:genetics*; D019066:Facies; D005260:Female; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D006801:Humans; D006984:Hypertrophy; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D032446:Myoblasts / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites
keywords: Uruguay; exons; gene; mutation; polymorphism, single nucleotide