TY - JOUR
T1 - Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy
AU - Scionti, Isabella
AU - Greco, Francesca
AU - Ricci, Giulia
AU - Govi, Monica
AU - Arashiro, Patricia
AU - Vercelli, Liliana
AU - Berardinelli, Angela
AU - Angelini, Corrado
AU - Antonini, Giovanni
AU - Cao, Michelangelo
AU - Di Muzio, Antonio
AU - Moggio, Maurizio
AU - Morandi, Lucia
AU - Ricci, Enzo
AU - Rodolico, Carmelo
AU - Ruggiero, Lucia
AU - Santoro, Lucio
AU - Siciliano, Gabriele
AU - Tomelleri, Giuliano
AU - Trevisan, Carlo Pietro
AU - Galluzzi, Giuliana
AU - Wright, Woodring
AU - Zatz, Mayana
AU - Tupler, Rossella
N1 - Funding Information:
We are indebted to all FSHD patients and their families for participating in this study. The Associazione Amici del Centro Dino Ferrari-University of Milan is gratefully acknowledged. We thank Paul D. Kaufman and Michael R. Green for their in-depth critique of the manuscript. DNA from Brazilian controls was kindly provided by Naila Lourenço and Antonia Cerqueira (Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Brazil). This work was supported by Telethon GUP08004 and GUP11009, by Association Française Contre les Myopathies 14339, by National Institute of Health-National Institutes of Neurological Disorders and Stroke grant RO1 NS047584, by Centros de Pesquisa, Inovação e Difusão/Fundação de Amparo à Pesquisa do Estado de São Paulo, by Institutos Nacionais de Ciência e Tecnologia, and by Conselho Nacional de Desenvolvimento Científico e Tecnológico.
PY - 2012/4/6
Y1 - 2012/4/6
N2 - Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.
AB - Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.
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U2 - 10.1016/j.ajhg.2012.02.019
DO - 10.1016/j.ajhg.2012.02.019
M3 - Article
C2 - 22482803
AN - SCOPUS:84859478913
SN - 0002-9297
VL - 90
SP - 628
EP - 635
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -