An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

Sagath, L.; Lehtokari, Vilma-Lotta; Välipakka, Salla; Udd, Bjarne; Wallgren‐Pettersson, Carina; Pelin, Katarina; Kiiski, Kirsi

doi:10.3233/jnd-170298

Cited by 17 publications

(27 citation statements)

References 18 publications

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“…The higher read‐depth facilitated CNV detection, and detection of variants within the triplicated regions of TTN and NEB without need for an additional Comparative Genomic Hybridisation array . Within our study, 4% of genetically diagnosed probands harbored a CNV. Although megabase scale CNVs may have been detected by aCGH, the others are likely too small to be detected.…”

Section: Discussionmentioning

confidence: 68%

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

Beecroft

Yau

Allcock

et al. 2020

Ann Clin Transl Neurol

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Objective To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center. Methods We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeqTM probe‐based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high‐coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician. Results Six hundred and sixty‐five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E‐9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes. Interpretation A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease‐specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under‐recognized pathogenic variants.

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Section: Discussionmentioning

confidence: 68%

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

Beecroft

Yau

Allcock

et al. 2020

Ann Clin Transl Neurol

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“…Samples from patients 2 and 3 were analysed on a custom comparative genomic hybridization array targeting the known NM genes and 175 other genes related to neuromuscular disorders [12]. Moreover, a SNP array, CytoScan HD (Affymetrix), was used in patient 3.…”

Section: Methodsmentioning

confidence: 99%

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy

et al. 2018

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Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15–25% of cases). In this report all known NM related genes were screened by Next Generation Sequencing in five Spanish patients in order to genetically confirm the clinical and histological diagnosis of NM. Four mutations in NEB (c.17779_17780delTA, c.11086A>C, c.21076C>T and c.2310+5G>A) and one mutation in ACTA1 (c.871A>T) were found in four patients. Three of the four mutations in NEB were novel. A cDNA sequencing assay of the novel variants c.17779_17780delTA, c.11086A>C and c.2310+5G>A revealed that the intronic variant c.2310+5G>A affected the splicing process. Mutations reported here could help clinicians and geneticists in NM diagnosis.

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“…A definite diagnosis of NEB related disease was most often achieved by a combination of denaturing high-performance liquid chromatography and Sanger sequencing (Lehtokari et al 2006). Later, next generation sequencing and microarray analysis became available and resulted in a large improvement in the diagnosis of diseases caused by mutations in NEB and other large genes, such as TTN (Böhm et al 2013;Kiiski et al 2016;Sagath et al 2018;Scoto et al 2013;Vasli and Laporte 2013;Zenagui et al 2018). These techniques were further developed in recent years to improve the capture and coverage of difficult areas, such as repeat regions in NEB, and the detection of insertions/deletions as well as copy number variations in TTN and NEB (Kiiski et al 2016;Sagath et al 2018;Zenagui et al 2018).…”

Section: Nebulin In Muscle Diseasementioning

confidence: 99%

Nebulin: big protein with big responsibilities

Yuen

Ottenheijm

2020

J Muscle Res Cell Motil

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Nebulin, encoded by NEB, is a giant skeletal muscle protein of about 6669 amino acids which forms an integral part of the sarcomeric thin filament. In recent years, the nebula around this protein has been largely lifted resulting in the discovery that nebulin is critical for a number of tasks in skeletal muscle. In this review, we firstly discussed nebulin's role as a structural component of the thin filament and the Z-disk, regulating the length and the mechanical properties of the thin filament as well as providing stability to myofibrils by interacting with structural proteins within the Z-disk. Secondly, we reviewed nebulin's involvement in the regulation of muscle contraction, cross-bridge cycling kinetics, Ca 2+-homeostasis and excitation contraction (EC) coupling. While its role in Ca 2+-homeostasis and EC coupling is still poorly understood, a large number of studies have helped to improve our knowledge on how nebulin affects skeletal muscle contractile mechanics. These studies suggest that nebulin affects the number of force generating actin-myosin cross-bridges and may also affect the force that each cross-bridge produces. It may exert this effect by interacting directly with actin and myosin and/or indirectly by potentially changing the localisation and function of the regulatory complex (troponin and tropomyosin). Besides unravelling the biology of nebulin, these studies are particularly helpful in understanding the patho-mechanism of myopathies caused by NEB mutations, providing knowledge which constitutes the critical first step towards the development of therapeutic interventions. Currently, effective treatments are not available, although a number of therapeutic strategies are being investigated.

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An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

Cited by 17 publications

References 18 publications

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy

Nebulin: big protein with big responsibilities

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