D4Z4 reduced allele in myopathic subjects with no FSHD phenotype: why inconsistency between molecular and clinical data should prompt us to further investigations.

Aim of the study. Chacacterization of different FSHD clinical subsets and/or more complex myopathic conditions among carriers of D4Z4 reduced allele (DRA) associated with atypical myopathic phenotypes. Materials and methods. Out of 751 consecutive index cases recruited from the Italian National Registry for FSHD, we identified 298 myopathic patients carrying DRA with 4-8 repats who did not present obvious FSHD phenotype. Re-evaluation of clinical data and depth molecular characterization of 4q35 region were performed. Results. Twenty-three carriers of 4-8 DRA presented myopathic features related to non-FSHD conditions. In this group we observed high clinical heterogeneity. In particular subjects displayed different combinations of clinical signs that were considered atypical for FSHD: 1) involvement of muscles that are not usually affected in FSHD, 2) sparing of muscles that are typically affected in FSHD, 3) additional clinical, genetic and instrumental features that are not included in the FSHD phenotype. In addition, Molecular analysis of the 4q35 subtelomeric haplotype of myopathic DRA patients did not reveal any molecular element enabling us to differentiate these patients from classical FSHD patients. In two patients, heterozygous mutations were found in CAV-3 and HSPB3 genes. Interestingly, these patients were sporadic and no other myopathic subjects were reported in the two families. Discussion and conclusions. Our study shows that not all myopathic patients carrying 4-8 DRA are affected by FSHD. We conclude that in myopathic carriers of 4q short allele who do not display a typical autosomal dominant FSHD additional molecular and clinical investigations should be performed for a more precise characterization of these patients. This approach will favor clinical diagnosis and genetic counseling.