Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Töpf, Ana; Johnson, Katherine; Bates, Adam; Phillips, Lauren; Chao, Katherine R.; England, Eleina; Laricchia, Kristen M.; Mullen, T.; Valkanas, Elise; Xu, Liwen; Bértoli, Marta; Blain, A.; Casasús, Ana B; Duff, Jennifer; Mroczek, Magdalena; Specht, Sabine; Lek, Monkol; Ensini, Monica; MacArthur, Daniel G.; Straub, V.

doi:10.1038/s41436-020-0840-3

Cited by 64 publications

(61 citation statements)

References 44 publications

(55 reference statements)

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“…All families characterized in this study were consanguineous and showed a recessive inheritance pattern. Three individuals (family A, B and C) were included in the MYO–SEQ project [ 11 ]. For these patients, whole exome sequencing (WES) was performed at the Broad Institute’s Genomics Platform, using Illumina exome capture on a cohort of >1800 patients with limb-girdle muscle weakness.…”

Section: Methodsmentioning

confidence: 99%

Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

Mroczek

Durmuş

Töpf

et al. 2020

Genes

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We identified the known c.1_9del mutation in the PLEC gene in four unrelated females from consanguineous families of Turkish origin. All individuals presented with slowly progressive limb-girdle weakness without any dermatological findings, and dystrophic changes observed in their muscle biopsies. Additionally, the neurological examination revealed ptosis, facial weakness, fatigability, and muscle cramps in all four cases. In two patients, repetitive nerve stimulation showed a borderline decrement and a high jitter was detected in all patients by single-fiber electromyography. Clinical improvement was observed after treatment with pyridostigmine and salbutamol was started. We further characterize the phenotype of patients with limb-girdle muscular dystrophy R17 clinically, by muscle magnetic resonance imaging (MRI) features and by describing a common 3.8 Mb haplotype in three individuals from the same geographical region. In addition, we review the neuromuscular symptoms associated with PLEC mutations and the role of plectin in the neuromuscular junction.

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Section: Methodsmentioning

confidence: 99%

Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

Mroczek

Durmuş

Töpf

et al. 2020

Genes

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“…For patient 1, we performed a targeted next‐generation sequencing panel for metabolic myopathies, and for other patients, whole‐exome sequencing was recommended. For patients 3, 5 and 6, whole‐exome sequencing analysis was conducted through the MYO‐SEQ project [8]). The MYO‐SEQ project is an international research collaboration that applied targeted whole‐exome sequencing to approximately 1000 patients with undiagnosed proximal muscle weakness [8].…”

Section: Methodsmentioning

confidence: 99%

Adult‐onset very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD)

Fatehi

Okhovat

Nilipour

et al. 2020

Euro J of Neurology

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Background and purpose: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD. Methods: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described. Results: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a nonfluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment. Conclusion: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.

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“…Exome sequencing was carried out on DNA extracted from blood in the framework of the MYO‐SEQ project (Töpf et al, 2020) by focusing on potential mutations in a list of selected 169 genes that are known to be associated with manifestation of neuromuscular disorders (list is available on request). This analysis revealed a homozygous mutation in exon 8 of the FLNC gene (hg19: chr7:128478771C>G; c.1325C>G; p.Pro442Arg) that would lead to exclusive expression of FLNC with a p.Pro442Arg substitution in Ig‐like domain 2 of the FLNC rod domain.…”

Section: Resultsmentioning

confidence: 99%

“…Exome sequencing and data analysis was performed as part of the MYO‐SEQ project (Töpf et al, 2020). Sanger sequencing was performed in DNA to confirm the detected variants.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

et al. 2020

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Filamin C (encoded by the FLNC gene) is a large actin‐cross‐linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z‐discs of cross‐striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal‐dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild‐type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild‐type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.

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Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Cited by 64 publications

References 44 publications

Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

Adult‐onset very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD)

First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

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