Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy

Enzo Ricci, Giulia Ricci, Isabella Scionti, Francesco Sera, Monica Govi, Roberto D'Amico, Ilaria Frambolli, Fabiano Mele, Massimiliano Filosto, Liliana Vercelli, Lucia Ruggiero, Angela Berardinelli, Corrado Angelini, Giovanni Antonini, Elisabetta Bucci, Michelangelo Cao, Jessica Daolio, Antonio Di Muzio, Rita Di Leo, Giuliana GalluzziLorenzo Maggi, Valerio Maruotti, Maurizio Moggio, Tiziana Mongini, Lucia Morandi, Ana Nikolic, Ebe Pastorello, Carmelo Rodolico, Lucio Santoro, Maura Servida, Gabriele Siciliano, Giuliano Tomelleri, Rossella Tupler

Risultato della ricerca: Contributo in rivistaArticolo in rivista

57 Citazioni (Scopus)

Abstract

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (≤ 8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1-3 repeats or 4-8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4-8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4-8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family's genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.
Lingua originaleEnglish
pagine (da-a)3408-3417
Numero di pagine10
RivistaBRAIN (ONLINE)
Volume136
DOI
Stato di pubblicazionePubblicato - 2013

Keywords

  • Adolescent
  • Adult
  • Aged
  • Chromosome Deletion
  • Chromosome Disorders
  • Chromosomes, Human, Pair 4
  • D4Z4 reduced allele
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Haplotypes
  • Homeodomain Proteins
  • Humans
  • Male
  • Middle Aged
  • Muscular Dystrophy, Facioscapulohumeral
  • Pedigree
  • Prognosis
  • Registries
  • Young Adult
  • disease expression
  • facioscapulohumeral muscular dystrophy
  • genotype–phenotype correlations
  • penetrance

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