0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

TEL.13 – Clinical and laboratory criteria for FSHD diagnosis in view of a national registry…
functional evaluation of each affected muscle group, was used to quantify the
severity of patients’ clinical phenotype.
Our goals were: a) to verify the correlation between phenotype (described
by FSHD score) and genotype, taking into account number and size of D4Z4
alleles. Correlation also considered age and sex; b) to test the effect of contraction
of D4Z4 in both chromosomes 4 on patients’ phenotype; c) to test the
FSHD score as a tool to describe the clinical phenotype in a single quantitative
parameter, suitable for statistical analysis.
Analysis of FSHD score in compound heterozygous patients revealed
that heterozygosity for FSHD-sized alleles contributed to a more severe phenotype
(FSHD score 7.4 ± 3.7) than the one of their relatives (FSHD score
1.8 ± 2.4) carrying a single deletion on chromosome 4. We also observed
that 16 cases (51%) carrying the deletion on a single chromosome 4 were
asymptomatic (FSHD total score equal to 0) or showed very low penetrant
phenotype (FSHD total score equal to 1). This was independent of age but
significantly more females than males result protected from developing the
disease.
Interestingly, compound heterozygous patients displayed a complete penetrance
of the disease (9 out of 9) and a more severe phenotype.
Collectively our data show that the presence of D4Z4 deleted alleles on
both chromosomes 4 correlate with a significantly more severe phenotype
than the one of relatives and patients with a single deleted allele from different
families.
CLINICAL PROTOCOL AND METHODS
Overview
This research proposal aims at providing the basis to design a standardized
approach to FSHD diagnosis and testing the possibility of defining
novel prognostic markers for FSHD through genotype-phenotype correlation
studies.
A dedicated specific software and a website for data management will be
designed by Fabrizio Montesi. Statistical analysis of the data will be performed
under the supervision of Roberto D’Amico, University of Modena and
Reggio Emilia.
Specific Aim 1.To define the clinical and molecular features of a large
Italian population of subjects affected by FSHD and to investigate the genotype-phenotype
correlation in FSHD.
1. Genotype-phenotype correlation in FSHD
Our aim is the definition of guidelines for an accurate and efficacious
diagnostic protocol and the validation and use of the FSHD clinical severity
score. On the basis of a very large number of index cases (1062), great competence
of the clinicians of the clinical consortium, and 15-year long expertise
on the molecular basis of FSHD, we decided to re-evaluate all cases we analyzed
from 1993 to present, in order to establish an effective approach to
FSHD clinical evaluation and molecular diagnosis in view of the most recent
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