A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing

Krahn, Martin; Biancalana, Valérie; Cerino, Mathieu; Perrin, Aurélien; Michel-Calemard, Laurence; Nectoux, Juliette; Leturcq, F.; Bouchet-Seraphin, C.; Acquaviva‐Bourdain, Cécile; Campana‐Salort, Emmanuelle; Molon, Annamaria; Urtizberea, Jon Andoni; Audic, Frédérique; Chabrol, B.; Pouget, Jean; Froissart, Roseline; Melki, Judith; Rendu, John; Petit, François; Métay, Corinne; Seta, Nathalie; Sternberg, Damien; Fauré, Julien; Cossée, Mireille

doi:10.1038/s41431-018-0305-1

Cited by 28 publications

(37 citation statements)

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“…Fourth, information about additional Sanger re-sequencing of suboptimally covered regions can be integrated into the coverage report of the initial short-read sequencing allowing easy tracing of sequencing experiments. To demonstrate the performance of CovReport, we used exome sequencing data for NA12878 to visualize the coverage of 40 genes on the extended Limb-Girdle Muscular Dystrophy (LGMD) gene list defined by the French National Network for Rare Neuromuscular Diseases [4]. Coverage module of…”

Section: Resultsmentioning

confidence: 99%

“…However, this goal is much harder to achieve for larger gene panels containing difficult to sequence genes. This is the case for the neuromuscular disorder field, since 33 out of 203 genes on the consensus myopathy gene lists [4] contain "dark" regions of the genome that are not easily accessible using standard short-read sequencing approaches [1]. Disease-causing variants in these regions can therefore be overlooked leading to a false negative molecular diagnostic result.…”

Section: Discussionmentioning

confidence: 99%

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A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

Gorokhov

Cerino

Bartoli

et al. 2019

Preprint

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In order to properly interpret the results of a diagnostic gene panel sequencing test, gene coverage needs to be taken into consideration. If coverage is too low, an additional re-sequencing test is needed to make sure that a pathogenic variant is not missed. To facilitate the interpretation of coverage data, we designed CovReport, a novel easy-to-use visualization tool. CovReport generates a concise coverage summary that allows one-glance assessment of the sequencing test performance. Both gene-level and exon-level coverage can be immediately appreciated and taken into consideration for further medical decisions. CovReport does not require complex installation and can thus be easily implemented in any diagnostic laboratory setting. A user-friendly interface generates a graphic summary of coverage that can be directly included in the diagnostic report. In addition to a stand-alone version, we also provide a command line version of CovReport that can be integrated into any bioinformatics pipeline. This flexible tool is now part of routine sequencing analysis at the Department of Medical Genetics at La Timone Hospital (Marseille, France). Availability and implementation: CovReport is available at http://jdotsoft.com/CovReport.php. It is implemented in Java and supported on Windows, Mac OS X and Linux.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

Gorokhov

Cerino

Bartoli

et al. 2019

Preprint

Self Cite

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“…To demonstrate the performance of CovReport, we used exome sequencing data for NA12878 to visualize the coverage of 40 genes on the extended Limb-Girdle Muscular Dystrophy (LGMD) gene list defined by the French National Network for Rare Neuromuscular Diseases 5 . Coverage module of VarAFT 5 was used to obtain exon coverage for these genes.…”

Section: Use Casementioning

confidence: 99%

“…4 Laboratory of Biochemistry, La Conception Hospital, AP-HM, Marseille, France. 5 These authors contributed equally: Jérémie Mortreux and Florence Riccardi. *email: svetlana.gorokhova@univ-amu.fr…”

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confidence: 99%

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

Gorokhov

Cerino

Mortreux

et al. 2020

Sci Rep

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in order to properly interpret the results of a diagnostic gene panel sequencing test, gene coverage needs to be taken into consideration. if coverage is too low, an additional re-sequencing test is needed to make sure that a pathogenic variant is not missed. to facilitate the interpretation of coverage data, we designed covReport, a novel easy-to-use visualization tool. covReport generates a concise coverage summary that allows one-glance assessment of the sequencing test performance. Both gene-level and exon-level coverage can be immediately appreciated and taken into consideration for further medical decisions. covReport does not require complex installation and can thus be easily implemented in any diagnostic laboratory setting. A user-friendly interface generates a graphic summary of coverage that can be directly included in the diagnostic report. in addition to a stand-alone version, we also provide a command line version of covReport that can be integrated into any bioinformatics pipeline. this flexible tool is now part of routine sequencing analysis at the Department of Medical Genetics at La timone Hospital (Marseille, france). covReport is available at http://jdotsoft.com/covReport.php. it is implemented in Java and supported on Windows, Mac oS X and Linux.

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“…Calpain3 acts in muscle sarcomere formation and remodeling (Duguez, Bartoli, and Richard 2006). CAPN3 is the most commonly mutated gene in patients presenting with Limb Girdle Muscular Dystrophy (Duno et al 2008), making it one the first genes to be sequenced as part of the diagnostic work up of patients with this type of myopathy (Krahn et al 2019). More than 400 unique pathogenic or likely pathogenic variants have been reported in CAPN3 gene so far (359 in LOVD (accessed December 2, 2019) and 555 variants in ClinVar (version November 27, 2019)).…”

Section: Introductionmentioning

confidence: 99%

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Dionnet

Defour

Silva

et al. 2020

Preprint

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Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the “minigene” functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.

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A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing

Cited by 28 publications

References 4 publications

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

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