0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
allele with size of 35 kb (8 D4Z4 units) or shorter, was considered pathognomonic.
However, among the myopathic (FSHD-like) cases we analyzed, 75
carry p13E-11 EcoRI alleles ranging between 38 and 45 kb in size (number of
repeat unit between 9 and 11) and represent approximately 7% of the positive
cases analyzed. Since alleles between 38 and 45 kb in size, when detected in
healthy subjects, are considered within the range of normality, we have
planned to re-evaluate all patients carrying 38-45 kb alleles who have developed
a clear myopathy through a standardized clinical investigation. This
study should allow a detailed definition of their clinical phenotype and, eventually,
the identification of common features, if any. Moreover this analysis
may facilitate the identification of factors that can influence the clinical outcome.
All selected subjects will be re-evaluated by the designed neurologist. We
expect this analysis to provide data useful to:
1) identify factors contributing to the disease onset;
2) define the risk of developing a muscular dystrophy when carrying alleles
of such size in a definite family. This study might also allow the identification
of large pedigrees suitable for linkage analysis in order to isolate genetic
factors that can influence the penetrance of the disease.
D. Analysis of 4qA/4qB distribution – It has been suggested that 4qB subtelomeres
contain elements that might prevent FSHD manifestation [Lemmers
et al. 2002, 2004; Thomas et al. 2006]. However, all published studies are
related to clinically affected subjects and do not consider the frequency of the
“ non-penetrant gene carriers ” carrying the 4qA allele in the analyzed FSHD
population. The study of the frequency of the 4qA/4qB alleles in over 600
FSHD families, in correlation with the results of clinical evaluation, will allow
to calculate the disease penetrance in relationship with the size of the deleted
allele and the 4qA/4qB subtelomeric polymorphisms.
The results of this study will allow us to verify the “ protective effect ” of
4qB alleles, and possibly strengthen the causal association between FSHD and
the presence of 4qA alleles telomeric to D4Z4 deleted alleles [Lemmers et al.
2004]. Clearly, confirmation that carriers of 4qB allele do not develop FSHD
will have positive implications for prognosis and genetic counseling. All 1062
subjects carrying a D4Z4 deleted allele (number of repeat unit fewer than 11,
p13E-11EcoRI fragment shorter than 45 kb) will be investigated for the
4qA/4qB allelic variant of chromosome 4.
E. Study of FSHD patients carrying two deleted alleles – Genotype−phenotype
studies conducted on six FSHD families in which compound heterozygotes or
homozygotes for two deleted alleles on chromosome 4 are contradictory
[Wohlgemuth et al. 2003, Tonini et al. 2004; Lemmers 2004]. The study by
Wohlgemuth et al. suggested a dosage effect of the two deleted alleles,
whereas the studies of Tonini et al. and Lemmers et al. indicated that the presence
of two alleles does not result in a more severe phenotype and that one of
the two alleles might not be pathogenic.
Our study, conducted on 7 families and 40 subjects (9 compound heterozygotes)
shows that the presence of two pathogenic alleles worsens the
776 2009