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.
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: Andrei Petrov; Iryna Pirozhkova; Gilles Carnac; Dalila Laoudj; Marc Lipinski; Yegor S Vassetzky Journal: Proc Natl Acad Sci U S A Date: 2006-04-21 Impact factor: 11.205
Authors: Richard J F L Lemmers; Mariëlle Wohlgemuth; Rune R Frants; George W Padberg; Eva Morava; Silvere M van der Maarel Journal: Am J Hum Genet Date: 2004-10-04 Impact factor: 11.025
Authors: J C de Greef; R J L F Lemmers; P Camaño; J W Day; S Sacconi; M Dunand; B G M van Engelen; S Kiuru-Enari; G W Padberg; A L Rosa; C Desnuelle; S Spuler; M Tarnopolsky; S L Venance; R R Frants; S M van der Maarel; R Tawil Journal: Neurology Date: 2010-10-26 Impact factor: 9.910
Authors: Richard J L F Lemmers; Marielle Wohlgemuth; Kristiaan J van der Gaag; Patrick J van der Vliet; Corrie M M van Teijlingen; Peter de Knijff; George W Padberg; Rune R Frants; Silvere M van der Maarel Journal: Am J Hum Genet Date: 2007-09-07 Impact factor: 11.025
Authors: Takako Iida Jones; Jennifer C J Chen; Fedik Rahimov; Sachiko Homma; Patricia Arashiro; Mary Lou Beermann; Oliver D King; Jeffrey B Miller; Louis M Kunkel; Charles P Emerson; Kathryn R Wagner; Peter L Jones Journal: Hum Mol Genet Date: 2012-07-13 Impact factor: 6.150