Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Ruggiero, Lucia; Mele, Fabiano; Manganelli, Fiore; Bruzzese, Dario; Ricci, Giulia; Vercelli, Liliana; Govi, Monica; Vallarola, Antonio; Tripodi, Silvia; Villa, Luísa; Muzio, Antonio Di; Scarlato, Marina; Bucci, Elisabetta; Antonini, Giovanni; Maggi, Lorenzo; Rodolico, Carmelo; Tomelleri, Giuliano; Filosto, Massimiliano; Previtali, Stefano C.; Angelini, Corrado; Berardinelli, Angela; Pegoraro, Elena; Moggio, Maurizio; Mongini, Tiziana; Siciliano, Gabriele; Santoro, Lucio; Tupler, Rossella

doi:10.1001/jamanetworkopen.2020.4040

Cited by 29 publications

(47 citation statements)

References 62 publications

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“…In particular, carriers of 7-8 DRA, until now considered in the classical FSHD range, present a clinical variability that is quite similar to that found among subjects carrying one 9 -10 DRA [9], which are instead considered borderline alleles [11]. Some genotype-phenotype studies suggest carriers 7-10 DRA have a low penetrance and, in this subgroup, the muscular impairment of carriers relatives is less severe than index cases [9,17,20]. By contrast carriers of 1-3 DRA present less significant differences [8].…”

Section: Introductionsupporting

confidence: 55%

“…Recently, through the use of the CCEF we clarified that there is a clinical phenotypic spectrum in molecularly homogeneous genetic subgroups. In particular, carriers of 7-8 DRA, until now considered in the classical FSHD range, present a clinical variability that is quite similar to that found among subjects carrying one 9 -10 DRA [9], which are instead considered borderline alleles [11]. Some genotype-phenotype studies suggest carriers 7-10 DRA have a low penetrance and, in this subgroup, the muscular impairment of carriers relatives is less severe than index cases [9,17,20].…”

Section: Introductionmentioning

confidence: 93%

“…Since the discovery of the D4Z4 locus for FSHD diagnosis it was clear that many different phenotypes and reduced Liliana Vercelli, Fabiano Mele and Lucia Ruggiero contributed equally to this work. penetrance [7][8][9][10][11][12][13][14][15][16][17] can be observed in people carrying a D4Z4 reduced allele (DRA). These features have substantially hindered the possibility of defining the progression modes and the natural history of FSHD [18,19] with critical consequences on clinical management.…”

Section: Introductionmentioning

confidence: 99%

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A 5-year clinical follow-up study from the Italian National Registry for FSHD

et al. 2020

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Background The natural history of facioscapulohumeral muscular dystrophy (FSHD) is undefined. Methods An observational cohort study was conducted in 246 FSHD1 patients. We split the analysis between index cases and carrier relatives and we classified all patients using the Comprehensive Clinical Evaluation Form (CCEF). The disease progression was measured as a variation of the FSHD score performed at baseline and at the end of 5-year follow-up (ΔFSHD score). Findings Disease worsened in 79.4% (112/141) of index cases versus 38.1% (40/105) of carrier relatives and advanced more rapidly in index cases (ΔFSHD score 2.3 versus 1.2). The 79.1% (38/48) of asymptomatic carriers remained asymptomatic. The highest ΔFSHD score (1.7) was found in subject with facial and scapular weakness at baseline (category A), whereas in subjects with incomplete phenotype (facial or scapular weakness, category B) had lower ΔFSHD score (0.6) p < 0.0001. Conclusions The progression of disease is different between index cases and carrier relatives and the assessment of the CCEF categories has strong prognostic effect in FSHD1 patients.

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Section: Introductionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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A 5-year clinical follow-up study from the Italian National Registry for FSHD

et al. 2020

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“…In the field of FSHD there are accumulating evidences that the reduction of D4Z4 repetitive elements is not per se sufficient to cause disease [2]. It is also definite that multiple phenotypes can be found in people carrying the same molecular markers including healthy people or subjects with other diseases [6,15].…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Williams Beuren syndrome critical region unmasks facioscapulohumeral muscular dystrophy

Rodolico

Politano

Portaro

et al. 2020

European Journal of Paediatric Neurology

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Among 1339 unrelated cases accrued by the Italian National Registry for facioscapulohumeral muscular dystrophy (FSHD), we found three unrelated cases who presented signs of Williams-Beuren Syndrome (WBS) in early childhood and later developed FSHD. All three cases carry the molecular defects associated with the two disorders. The rarity of WBS and FSHD, 1 in 7500 and 1 in 20,000 respectively, makes a random association of the two diseases unlikely. These cases open novel and unexpected interpretation of genetic findings. The nonrandom association of both FSHD and WBS points at a gene co-expression network providing hints for the identification of modules and functionally enriched pathways in the two conditions.

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“…FSHD is characterized by reduced penetrance and wide variability in the clinical expression among patients and within families 10 – 13 . Indeed, the widespread use of molecular analysis to diagnose FSHD has revealed various phenotypes in subjects carrying D4Z4 alleles of reduced size, including atypical or incomplete phenotypes 12 – 19 .…”

Section: Introductionmentioning

confidence: 99%

Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis

Ricci

Mele

Govi

et al. 2020

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Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

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Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Cited by 29 publications

References 62 publications

A 5-year clinical follow-up study from the Italian National Registry for FSHD

A 5-year clinical follow-up study from the Italian National Registry for FSHD

Deletion of the Williams Beuren syndrome critical region unmasks facioscapulohumeral muscular dystrophy

Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis

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