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Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling
  1. Isabella Scionti1,
  2. Greta Fabbri1,
  3. Chiara Fiorillo2,
  4. Giulia Ricci3,
  5. Francesca Greco1,
  6. Roberto D'Amico4,
  7. Alberto Termanini1,
  8. Liliana Vercelli5,
  9. Giuliano Tomelleri6,
  10. Michelangelo Cao7,
  11. Lucio Santoro8,
  12. Antonio Percesepe9,
  13. Rossella Tupler1,10
  1. 1Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
  2. 2Fondazione Stella Maris IRCCS, Pisa, Italy
  3. 3Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
  4. 4Unit of Statistics, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
  5. 5Center for Neuromuscular Diseases, Department of Neuroscience, University of Turin, Torino, Italy
  6. 6Department of Neurological Sciences and Vision, University of Verona, Verona, Italy
  7. 7Department of neurosciences, University of Padua, Padua, Italy
  8. 8Department of Neurological Sciences, University ‘Federico II’, Naples, Napoli, Italy
  9. 9Department of Mother & Child, University of Modena and Reggio Emilia, Modena, Italy
  10. 10Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  1. Correspondence to Professor Rossella Tupler, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, Modena 41125, Italy; rossella.tupler{at}


Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS.

Methods and results Through the Italian National Registry for FSHD (INRF), genotype–phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%.

Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.

  • Facioscapulohumeral muscular dystrophy
  • D4Z4-reduced alleles
  • genetic counselling
  • polymorphisms
  • compound heterozygote
  • genetics
  • genetic epidemiology
  • microarray
  • molecular genetics
  • clinical genetics
  • chromosomal
  • diagnostics
  • ethics
  • genetic screening/counselling
  • muscle disease
  • neuromuscular disease

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  • Funding This work was supported by Telethon GUP08004, AFM 14339 and NIH-NINDS grant number RO1 NS047584.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The Modena ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement There are no unpublished data from the study presented. All clinical and molecular data are included in the supplementary file.