title: Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.
abstract: OBJECTIVE
  Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 repeat array on chromosome 4. So far, homozygosity or compound heterozygosity for FSHD alleles has not been described, and it has been debated whether the absence of such subjects is because of the rarity or the lethality of the disorder.
  
  
  METHODS
  Two unrelated families in which the probands are compound heterozygous for two FSHD-sized alleles were studied. Clinical examination, pulsed-field gel electrophoresis (PFGE) studies of DNA with probes proximal and distal to D4Z4, and cytogenetic analysis of metaphase chromosomes by FISH were performed.
  
  
  RESULTS
  Complementary molecular and cytogenetic approaches confirmed the chromosome 4qA origin of all FSHD-sized repeat arrays that segregate in the families.
  
  
  CONCLUSIONS
  Heterozygosity for FSHD-sized alleles is compatible with life in men and women. A possible dosage effect was observed in both probands in whom each 4qA allele contributed to the FSHD phenotype. Because at least one of the FSHD alleles in both families showed an unusual low penetrance, the authors propose that susceptibility for FSHD is partly determined by intrinsic properties of the disease allele other than the residual D4Z4 repeat size alone.
authors.affiliation: Department of Neurology, University Medical Center Nijmegen, The Netherlands. m.wohlgemuth@neuro.umcn.nl
authors.forename: M
authors.initials: M
authors.lastname: Wohlgemuth
authors.forename: R J
authors.initials: RJ
authors.lastname: Lemmers
authors.forename: E L
authors.initials: EL
authors.lastname: van der Kooi
authors.forename: M J
authors.initials: MJ
authors.lastname: van der  Wielen
authors.forename: P G
authors.initials: PG
authors.lastname: van Overveld
authors.forename: H
authors.initials: H
authors.lastname: Dauwerse
authors.forename: E
authors.initials: E
authors.lastname: Bakker
authors.forename: R R
authors.initials: RR
authors.lastname: Frants
authors.forename: G W
authors.initials: GW
authors.lastname: Padberg
authors.forename: S M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000368:Aged; D000483:Alleles; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D020732:Cytogenetic Analysis; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D018628:Gene Dosage; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping