title: Clinical and genetic characterization of manifesting carriers of DMD mutations.
abstract: Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Soltanzadeh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.forename: Diane
authors.initials: D
authors.lastname: Dunn
authors.forename: Andrew
authors.initials: A
authors.lastname: von Niederhausern
authors.forename: Olga L
authors.initials: OL
authors.lastname: Gurvich
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Jacinda B
authors.initials: JB
authors.lastname: Sampson
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Anne M
authors.initials: AM
authors.lastname: Connolly
authors.forename: Julaine M
authors.initials: JM
authors.lastname: Florence
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: Livija
authors.initials: L
authors.lastname: Medne
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Wong
authors.forename: Michael D
authors.initials: MD
authors.lastname: Sussman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zonana
authors.forename: Karen
authors.initials: K
authors.lastname: Kovak
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Gospe
authors.forename: Eduard
authors.initials: E
authors.lastname: Gappmaier
authors.forename: Laura E
authors.initials: LE
authors.lastname: Taylor
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
mesh_terms: D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D006334:Heart Function Tests; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics / Q000502:physiology; D049951:X Chromosome Inactivation / Q000235:genetics; D055815:Young Adult
chemical_list: C484258:DMD protein, human; D016189:Dystrophin