title: Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Scionti
authors.forename: Francesca
authors.initials: F
authors.lastname: Greco
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.forename: Monica
authors.initials: M
authors.lastname: Govi
authors.forename: Patricia
authors.initials: P
authors.lastname: Arashiro
authors.forename: Liliana
authors.initials: L
authors.lastname: Vercelli
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Antonini
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cao
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Muzio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.forename: Lucia
authors.initials: L
authors.lastname: Ruggiero
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.forename: Carlo Pietro
authors.initials: CP
authors.lastname: Trevisan
authors.forename: Giuliana
authors.initials: G
authors.lastname: Galluzzi
authors.forename: Woodring
authors.initials: W
authors.lastname: Wright
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Rossella
authors.initials: R
authors.lastname: Tupler
mesh_terms: D000328:Adult; D000368:Aged; D001938:Brazil / Q000453:epidemiology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000175:diagnosis* / Q000235:genetics*; D011110:Polymorphism, Genetic; D020080:Tandem Repeat Sequences / Q000235:genetics*