Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy

Kuhn, Marius; Gläser, Dieter; Joshi, Pushpa Raj; Zierz, Stephan; Wenninger, Stephan; Schöser, Benedikt; Deschauer, Marcus

doi:10.1007/s00415-016-8036-0

Cited by 59 publications

(69 citation statements)

References 26 publications

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“…NGS had successfully found causative mutations in many of the monogenic diseases. Like other medical fields, the NGS can be used to identify genes involved in LGMDs and such an application will tremendously broaden our knowledge of LGMDs (Kuhn et al, ; Reddy et al, ; Savarese et al, ; Yu et al, ).…”

Section: Ngs and Lgmdsmentioning

confidence: 99%

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Taghizadeh

Rezaee

Barreto

et al. 2018

Journal Cellular Physiology

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Limb‐girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and arms. Signs and symptoms may begin at any age and usually worsen by time. LGMDs are autosomal disorders with different types and their prevalence is not the same in different areas. New technologies such as next‐generation sequencing can accelerate their diagnosis. Several important pathological mechanisms that are involved in the pathology of the LGMD include abnormalities in dystrophin–glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions. Here, we provide a comprehensive review that integrates LGMD clinical manifestations, prevalence, and some pathological mechanisms involved in LGMDs.

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Section: Ngs and Lgmdsmentioning

confidence: 99%

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Taghizadeh

Rezaee

Barreto

et al. 2018

Journal Cellular Physiology

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“…A further support of this result came from next generation sequencing of unclassified LGMD cases selected following negative protein testing. The diagnosis of dysferlinopathy was due to the high detection rate of absent dysferlin protein and subsequent Sanger sequencing …”

Section: Genetic Diagnosismentioning

confidence: 99%

Progress and challenges in diagnosis of dysferlinopathy

Fanin

Angelini

2016

Muscle Nerve

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Dysferlin-deficient limb girdle muscular dystrophy type 2B, distal Miyoshi myopathy, and other less frequent phenotypes are a group of recessive disorders called dysferlinopathies. They are characterized by wide clinical heterogeneity. To diagnose dysferlinopathy, a clinical neuromuscular workup, including electrophysiological and muscle imaging investigations, is essential to support subsequent laboratory testing. Increased serum creatine kinase levels, distal or proximal muscle weakness, and myalgia with onset in the second or third decades are the main clinical features of the disease. In muscle biopsies, severe dysferlin deficiency by immunoblot or its abnormal localization by immunohistochemistry are the gold standard, as they have a high diagnostic value. Dysferlin testing on monocytes is a valuable alternative to muscle immunoblotting. Molecular techniques for gene mutation detection, such as next generation sequencing, have improved the genetic diagnosis, which is crucial for treatment and genetic counselling. Muscle Nerve 54: 821-835, 2016.

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“…17 Previously, multiple targeted disease-specific panel NGS efforts including that of LGMD for molecular diagnostics were performed. 12,[18][19][20][21][22][23][24] But to our knowledge, this study uniquely surpasses them by recruiting a very large number (4656) of patients clinically suspected of a specific disorder (LGMDs) in the USA irrespective of ethnicities. We aimed to provide complete molecular diagnosis to this large group of clinically characterized LGMD patients.…”

Section: Introductionmentioning

confidence: 99%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

145

165

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ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

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Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy

Cited by 59 publications

References 26 publications

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Progress and challenges in diagnosis of dysferlinopathy

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

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