title: Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging.
abstract: Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Animesh
authors.initials: A
authors.lastname: Tandon
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: John L
authors.initials: JL
authors.lastname: Jefferies
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Chet R
authors.initials: CR
authors.lastname: Villa
authors.affiliation: The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Kan N
authors.initials: KN
authors.lastname: Hor
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Wong
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Gao
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.affiliation: The Heart and Vascular Center at the Christ Hospital, Cincinnati, Ohio.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mazur
authors.affiliation: Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fleck
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Sticka
authors.affiliation: Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Michael.Taylor1@cchmc.org.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D016189:Dystrophin; D004247:DNA