Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

Xi, Jianying; Blandin, Gaëlle; Lu, Jiahong; Luo, Sushan; Zhu, Wenhua; Béroud, Christophe; Pécheux, Christophe; Labelle, Véronique; Levy, Nicolas; Urtizberea, Jon Andoni; Zhao, Chongbo; Krahn, Martin

doi:10.4103/0028-3886.149386

Cited by 27 publications

(13 citation statements)

References 13 publications

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“…Korea (Shin et al, 2015), China (Jin et al, 2016;Xi et al, 2014), Iran (Fatehi et al, 2015), France (Krahn et al, 2009), as well as from an international multicenter study (Harris et al, 2016), demonstrating the genetic character in each population including the existence of have been reported to be located deep in intronic regions (Dominov et al, 2019). Hence, RNA analysis combined with genomic DNA will be needed to characterize undiagnosed cases.…”

Section: Discussionmentioning

confidence: 99%

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

et al. 2020

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Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb‐girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

et al. 2020

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“…2,7,23 One-third of patients have nonsense mutations, indicating that nonsense read-through therapies, now licensed in Europe for use in Duchenne muscular dystrophy, may be a potential therapy for some patients with dysferlinopathy.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Outcome Study for dysferlinopathy

et al. 2016

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Objective:To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.Methods:The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.Results:There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.Conclusions:These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

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“…Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by mutations in dysferlin( DYSF ) gene showing marked clinical heterogeneity. [ 1 2 3 4 5 6 ] The most common phenotypes of dysferlinopathy are proximal limb weakness (limb girdle muscular dystrophy type 2B [LGMD2B])[ 1 ] and distal myopathy (Miyoshi myopathy [MM]). [ 2 ] However, other atypical symptoms such as hyperCKemia,[ 7 ] distal anterior compartment myopathy,[ 8 ] and proximodistal myopathy (PDM)[ 3 ] are not rare and can have a congenital onset.…”

Section: Introductionmentioning

confidence: 99%

“…[ 18 ] Exonic rearrangements had been reported on rare occasions and were identified as the second disease-causing mutation in 5 of 12 patients by multiplex ligation-dependent probe amplification (MLPA). [ 19 ] Given the high frequency of patients with only one pathogenic mutation (the proportion varied from 12.5% to 34.0% in previous studies),[ 4 5 18 ] it is necessary to carry out MLPA testing in these patients as a supplementary tool in the routine screening for DYSF gene mutations.…”

Section: Introductionmentioning

confidence: 99%

Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy

Jin

Zhang

et al. 2016

Chinese Medical Journal

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Background:Dysferlinopathy is caused by mutations in the dysferlin (DYSF) gene. Here, we described the genetic features of a large cohort of Chinese patients with this disease.Methods:Eighty-nine index patients were included in the study. DYSF gene analysis was performed by Sanger sequencing in 41 patients and targeted next generation sequencing (NGS) in 48 patients. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect exon duplication/deletion in patients with only one pathogenic mutation.Results:Among the 89 index patients, 79 patients were demonstrated to carry two disease-causing (73 cases) or possibly disease-causing mutations (6 cases), including 26 patients with homozygous mutations. We identified 105 different mutations, including 59 novel ones. Notably, in 13 patients in whom only one pathogenic mutation was initially found by Sanger sequencing or NGS, 3 were further identified to carry exon deletions by MLPA. The mutations identified in this study appeared to cluster in the N-terminal region. Mutation types included missense mutations (30.06%), nonsense mutations (17.18%), frameshift mutations (30.67%), in-frame deletions (2.45%), intronic mutations (17.79%), and exonic rearrangement (1.84%). No genotype-phenotype correlation was identified.Conclusions:DYSF mutations in Chinese patients clustered in the N-terminal region of the gene. Exonic rearrangements were found in 23% of patients with only one pathogenic mutation identified by Sanger sequencing or NGS. The novel mutations found in this study greatly expanded the mutational spectrum of dysferlinopathy.

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Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

Abstract: Our study underlines clinical heterogeneity and a high proportion of novel mutations in Chinese patients affected with dysferlinopathy.

Cited by 27 publications

References 13 publications

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

The Clinical Outcome Study for dysferlinopathy

Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy

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