From the experience of the Italian National Registry a novel tool to dissect the phenotypic complexity of facioscapulohumeral muscular dystrophy. the comprehensive clinical evaluation form

Background and aims: For the last 20 years, the diagnosis of facioscapulohumeral muscular dystrophy (FSHD) has been confirmed by the detection of one D4Z4 allele with a reduced number (≤ 8) of repeats at 4q35. In the meantime, several atypical phenotypes have been observed among D4Z4 reduced allele (DRA) carriers sometimes with unexpected mode of inheritance. In some cases the high frequency of FSHD molecular signature, also detected in healthy individuals and in asymptomatic relatives of probands, might have influenced diagnosis because of a biased correlation between a generic ‘myopathic’ phenotype and the detection of a DRA. There is therefore the need to generate tools that support diagnosis and genetic counseling in FSHD. Methods: The Italian Clinical Network developed the first FSHD clinical form in 2009; since then we systematically analyzed distribution of muscle impairment in over 500 index cases and 300 families and populate the Italian National Registry for FSHD (INRF) with standardized clinical information on certified FSHD patients and families. Based on our six-year experience, we designed and validated a Comprehensive Clinical Evaluation Form (CCEF), defining phenotypic categories by the combination of different clinical features. Results: Through the CCEF we classify: category A, subjects with typical FSHD phenotype; category B, subjects with incomplete FSHD phenotype; category C, asymptomatic subjects, and category D, myopathic subjects without typic FSHD features. Conclusion: We propose the widespread use of CCEF to ameliorate the classification of patients and families, to generate information to unravel the genetic complexity of FSHD, and to serve as a major tool for trial readiness. Disclosure: Supported by Telethon Italy, Grant GUP13012,