Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number ofKpnI repeats at the 4q35 locus and clinical phenotype

Ricci, Enzo; Galluzzi, G.; Deidda, G.; Cacurri, S.; Colantoni, Luca; Merico, Barbara; Piazzo, N.; Servidei, Serenella; Vigneti, Eliana; Pasceri, V.; Silvestri, Gabriella; Mirabella, Massimiliano; Mangiola, Fortunato; Tonali, P.; Felicetti, L.

doi:10.1002/1531-8249(199906)45:6<751::aid-ana9>3.0.co;2-m

Cited by 267 publications

(249 citation statements)

References 33 publications

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“…Patients were graded by the FSHD clinical score26 and the age‐adjusted clinical severity scale 27, 28. Both parents were assessed clinically, and the clinical severity scale27 was determined.…”

Section: Methodsmentioning

confidence: 99%

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

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Schreuder

Alfen

et al. 2018

Annals of Neurology

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ObjectiveFacioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood.MethodsWe performed a nationwide, single‐investigator, natural history study on FSHD in childhood.ResultsMultiple‐source recruitment resulted in 32 patients with FSHD (0–17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6‐minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early‐onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2–9), and 14% of the mutations were de novo.InterpretationFSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635–645

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Section: Methodsmentioning

confidence: 99%

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Goselink

Schreuder

Alfen

et al. 2018

Annals of Neurology

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“…25 Genetic analysis showed that he carries a permissive allele of 13 D4Z4 units and the D4Z4 methylation analysis revealed a methylation level of 9% (Delta1 score − 28%), which is consistent with the diagnosis of FSHD2. SMCHD1 Sanger sequencing identified two SMCHD1 variants in exon 21 in individual 947-201 (Table 1).…”

Section: Two Smchd1 Variants In Cis In Rf947mentioning

confidence: 62%

“…Clinical assessment of disease severity was performed using the 10-point (0: unaffected; 10: wheelchair bound) standardized Clinical Severity Score (CSS). 25 The first family (Rf947) consists of a single patient living in the United States of America. We were not able to get additional family information from this individual.…”

Section: Materials and Methods Subjectsmentioning

confidence: 99%

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

et al. 2015

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Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 functionaffecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

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“…These families were subjected to further clinical examinations and molecular analyses. A ten-grade clinical severity (CS) scale score 14 was used to evaluate the phenotypes of the affected individuals. To identify the chromosomal origin of these fragments, NotI-digested DNA was hybridized to the chromosome 4-specific probe B31, as previously reported.…”

Section: Subjects and Pfge-based Dna Analysismentioning

confidence: 99%

Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population

Wang

Maarel

et al. 2010

Eur J Hum Genet

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Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy with markedly clinical variability and complex genetic cause. Several reports pertaining to the Caucasian population have confirmed that there are 4qA and 4qB variants of the 4qter subtelomere, and FSHD is uniquely associated with the 4qA variant. However, few data relevant to the Chinese population have been published. In present paper, detailed clinical and genetic re-evaluations were performed in members of four special families who had been initially diagnosed as atypical or asymptomatic FSHD based only on the D4Z4 repeat length analysis. The FSHD-sized D4Z4 repeats in the probands from families 1, 2 and 3 were identified as 4qB variants. These patients were further confirmed as limb-girdle muscular dystrophy (LGMD2) or myotonic dystrophy (DM1) by molecular analyses. Specifically, we identified a 4qB variant on chromosome 10 in the healthy members of the fourth FSHD family with complex D4Z4 rearrangements of two exchanged repeat arrays. For the first time, we demonstrated in the Chinese population that D4Z4 contractions on the 4qB variant do not cause FSHD and 4qB variant on chromosome 10 might also represent intermediate structures in the transition from 4q to 10q. Furthermore, our results emphasize that D4Z4 repeat length analysis alone is not sufficient for the diagnosis of FSHD, especially when used as an exclusion criterion. This analysis should be accompanied by 4qA/4qB variant determination and integrated chromosome assignments, especially in patients with obscure and unclassified myopathies similar to atypical forms of FSHD.

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Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number ofKpnI repeats at the 4q35 locus and clinical phenotype

Cited by 267 publications

References 33 publications

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population

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