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TEL.13 – Clinical and laboratory criteria for FSHD diagnosis in view of a national registry…
Can prognostic tools be developed?
FSHD is a progressive disorder. At present, the progression of the disease
is unpredictable and it is impossible to address patients’ questions in
this regard. Through the design of a clinical evaluation score, we plan to
perform the quantitative evaluation of more than 1000 patients, searching
for criteria, if any, to predict the clinical outcome of the disease in an individual
patient.
Which factors may influence the FSHD clinical phenotype?
FSHD onset and progression are unpredictable and low penetrance is
observed. FSHD can be considered a mendelian disorder with complex phenotype.
Intriguingly, the observation that FRG1 over-expression leads to aberrant
gene splicing supports the hypothesis that FSHD phenotype might result
from a cascade of molecular events triggered by D4Z4 deletion. It is thus
likely that several factors might contribute to the disease pathogenesis. We
plan to collect anamnestic records and clinical data from a large number of
patients and families using standardized methods. This approach will allow
us to gather statistically significant information that will facilitate the identification
of factors that influence the clinical phenotype. The identification of
such factors will provide useful information of immediate interest for patients
in terms of prevention and prognosis.
Which role exert sex, age and alleles size on FSHD penetrance?
Gender as well the D4Z4 repeat number seem to significantly affect the
clinical outcome of FSHD. However up-to-date values of penetrance are not
available, and genetic counseling cannot address frequently asked questions
regarding this point. The availability of a large number of patients and families
will allow us to estimate the penetrance of the genetic defect with respect
to sex, age, and allele size. This analysis will provide useful tools to assist
patients in their reproductive decisions.
Is FSHD a genetically heterogeneous disorder?
In the early nineties FSHD genetic heterogeneity was described based on
the fact that p13E-11 hybridization failed to detect the EcoRI short allele in a
number of FSHD families. However, in those families it has been recently
demonstrated that the apparent absence of the short EcoRI fragment was due
to the presence of a deletion of the region proximal to the D4Z4 repeat array
that encompasses the p13E-11probe. At present, no FSHD families linked to
other chromosomal loci have been described. Our studies will further characterize
a cohort of patients displaying FSHD clinical features and failing to
exhibit short D4Z4 alleles. Our analysis should define the existence of genetic
heterogeneity in FSHD.
In summary, the proposed studies will:
1) allow the classification of FSHD clinical features in view of patients’
molecular characterization;
2) identify factors influencing the disease clinical expression;
3) update the penetrance value in view of age, sex and allele size;
4) verify the presence of genetic heterogeneity in FSHD.
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