Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy

Isabella Scionti, Francesca Greco, Giulia Ricci, Monica Govi, Patricia Arashiro, Liliana Vercelli, Angela Berardinelli, Corrado Angelini, Giovanni Antonini, Michelangelo Cao, Antonio Di Muzio, Maurizio Moggio, Lucia Morandi, Enzo Ricci, Carmelo Rodolico, Lucia Ruggiero, Lucio Santoro, Gabriele Siciliano, Giuliano Tomelleri, Carlo Pietro Trevisan & 4 others Giuliana Galluzzi, Woodring Wright, Mayana Zatz, Rossella Tupler

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)628-635
Number of pages8
JournalAmerican Journal of Human Genetics
Volume90
Issue number4
DOIs
StatePublished - Apr 6 2012

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Facioscapulohumeral Muscular Dystrophy
Muscular Dystrophies
Population
Alleles
Haplotypes
Tandem Repeat Sequences
Genetic Counseling
Muscular Diseases
Prenatal Diagnosis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy. / Scionti, Isabella; Greco, Francesca; Ricci, Giulia; Govi, Monica; Arashiro, Patricia; Vercelli, Liliana; Berardinelli, Angela; Angelini, Corrado; Antonini, Giovanni; Cao, Michelangelo; Di Muzio, Antonio; Moggio, Maurizio; Morandi, Lucia; Ricci, Enzo; Rodolico, Carmelo; Ruggiero, Lucia; Santoro, Lucio; Siciliano, Gabriele; Tomelleri, Giuliano; Trevisan, Carlo Pietro; Galluzzi, Giuliana; Wright, Woodring; Zatz, Mayana; Tupler, Rossella.

In: American Journal of Human Genetics, Vol. 90, No. 4, 06.04.2012, p. 628-635.

Research output: Contribution to journalArticle

Scionti, I, Greco, F, Ricci, G, Govi, M, Arashiro, P, Vercelli, L, Berardinelli, A, Angelini, C, Antonini, G, Cao, M, Di Muzio, A, Moggio, M, Morandi, L, Ricci, E, Rodolico, C, Ruggiero, L, Santoro, L, Siciliano, G, Tomelleri, G, Trevisan, CP, Galluzzi, G, Wright, W, Zatz, M & Tupler, R 2012, 'Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy', American Journal of Human Genetics, vol. 90, no. 4, pp. 628-635. https://doi.org/10.1016/j.ajhg.2012.02.019
Scionti, Isabella ; Greco, Francesca ; Ricci, Giulia ; Govi, Monica ; Arashiro, Patricia ; Vercelli, Liliana ; Berardinelli, Angela ; Angelini, Corrado ; Antonini, Giovanni ; Cao, Michelangelo ; Di Muzio, Antonio ; Moggio, Maurizio ; Morandi, Lucia ; Ricci, Enzo ; Rodolico, Carmelo ; Ruggiero, Lucia ; Santoro, Lucio ; Siciliano, Gabriele ; Tomelleri, Giuliano ; Trevisan, Carlo Pietro ; Galluzzi, Giuliana ; Wright, Woodring ; Zatz, Mayana ; Tupler, Rossella. / Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 4. pp. 628-635.
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AU - Vercelli, Liliana

AU - Berardinelli, Angela

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AU - Di Muzio, Antonio

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AU - Morandi, Lucia

AU - Ricci, Enzo

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AU - Santoro, Lucio

AU - Siciliano, Gabriele

AU - Tomelleri, Giuliano

AU - Trevisan, Carlo Pietro

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AU - Wright, Woodring

AU - Zatz, Mayana

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