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- Title
Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy.
- Authors
Ruggiero, Lucia; Mele, Fabiano; Manganelli, Fiore; Bruzzese, Dario; Ricci, Giulia; Vercelli, Liliana; Govi, Monica; Vallarola, Antonio; Tripodi, Silvia; Villa, Luisa; Di Muzio, Antonio; Scarlato, Marina; Bucci, Elisabetta; Antonini, Giovanni; Maggi, Lorenzo; Rodolico, Carmelo; Tomelleri, Giuliano; Filosto, Massimiliano; Previtali, Stefano; Angelini, Corrado
- Abstract
Key Points: Question: What are the phenotypes expressed among patients with facioscapulohumeral muscular dystrophy (FHSD) who are carriers of D4Z4 reduced allele with 7 to 8 repeat units? Findings: In this cross-sectional study of 187 probands and 235 relatives who carry a D4Z4 reduced allele with 7 to 8 repeat units, 47.1% of probands did not have the classic FSHD phenotype, and 52.8% of the carrier relatives were nonpenetrant. In 106 families, 18.9% had a member with autosomal dominant FSHD, whereas in 34.9%, the proband was the only participant expressing a myopathic phenotype. Meaning: The findings of this study suggest that knowledge of phenotypic variation in the expression of D4Z4 reduced allele with 7 to 8 repeat units in individuals with FSHD could be informative for clinical management and genetic counseling. This cross-sectional study investigates the clinical expression of facioscapulohumeral muscular dystrophy (FSHD) in the genetic subgroup of carriers of D4Z4 reduced allele with 7 to 8 repeat units. Importance: Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). Objective: To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). Design, Setting, and Participants: This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. Main Outcomes and Measures: The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). Results: A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD. Conclusions and Relevance: This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.
- Subjects
ITALY; AGE distribution; ALLELES; CHI-squared test; CONFIDENCE intervals; MEDICAL cooperation; RESEARCH; SEX distribution; STATISTICS; T-test (Statistics); PHENOTYPES; GENETIC testing; DATA analysis; FACIOSCAPULOHUMERAL muscular dystrophy; CROSS-sectional method; SEVERITY of illness index; DATA analysis software; DESCRIPTIVE statistics; SEQUENCE analysis; ONE-way analysis of variance
- Publication
JAMA Network Open, 2020, Vol 3, Issue 5, pe204040
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2020.4040