Phenotypic and molecular characterization of FSHD families: a systematic approach towards trial readiness

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary myopathy. FSHD is characterized by progressive, asymmetric atrophy and weakness of a highly selective set of muscle groups, with wide inter- and intra-familial variability of clinical expression. The disease has been linked to reduction of D4Z4 repeat units on chromosome 4q35. It has been proposed that D4Z4 reduced alleles (DRA) must be associated with specific haplotypes to cause FSHD. However, the studies performed on Italian National Registry for FSHD (INRF, www.fshd.it), that has been established in 2007 by Italian Clinical Network for FSHD (ICNF), showed that 1.3% of healthy subjects from general population carry this molecular signature and that probably additional factors might be necessary to develop FSHD. The large collection of FSHD in the Italian Registry demonstrates the impact of the disease and provides a valuable resource for research. The aim of this Italian multicenter project will be: to classify FSHD patients and families in homogeneous sub-groups on the basis of phenotypic and genetic features; to investigate the natural history of the disease through the prospective clinical evaluation of patients; to seek modifier loci or new genes through whole exome sequencing and candidate gene approach. The Research Group expect to provide useful tools for diagnostic assessment and clinical care, supporting genetic counseling and prognosis in FSHD. The accurate description of clinical features will constitute the basis for future research aimed at increasing the understanding of clinical and genetic complexity of FSHD and at identifying outcomes of interests for patients and clinicians to be used in clinical trials.