Facioscapulohumeral muscular dystrophy: New insights from compound heterozygotes and implication for prenatal genetic counselling

Isabella Scionti, Greta Fabbri, Chiara Fiorillo, Giulia Ricci, Francesca Greco, Roberto D'Amico, Alberto Termanini, Liliana Vercelli, Giuliano Tomelleri, Michelangelo Cao, Lucio Santoro, Antonio Percesepe, Rossella Tupler

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)171-178
Number of pages8
JournalJournal of Medical Genetics
Volume49
Issue number3
DOIs
Publication statusPublished - Mar 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Scionti, I., Fabbri, G., Fiorillo, C., Ricci, G., Greco, F., D'Amico, R., Termanini, A., Vercelli, L., Tomelleri, G., Cao, M., Santoro, L., Percesepe, A., & Tupler, R. (2012). Facioscapulohumeral muscular dystrophy: New insights from compound heterozygotes and implication for prenatal genetic counselling. Journal of Medical Genetics, 49(3), 171-178. https://doi.org/10.1136/jmedgenet-2011-100454