CoNVaDING: Single Exon Variation Detection in Targeted NGS Data

Johansson, Lennart; Dijk, Freerk van; Boer, Eddy N. de; Dijk-Bos, K. K. van; Jongbloed, Jan D. H.; Hout, Annemieke H. van der; Westers, Helga; Sinke, Richard J.; Swertz, Morris A.; Sijmons, Rolf H.; Sikkema‐Raddatz, Birgit

doi:10.1002/humu.22969

Cited by 80 publications

(76 citation statements)

References 22 publications

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“…Under such conditions, targeted NGS shows its advantages compared with Sanger sequencing of every single gene. It is also noteworthy that gross deletions or duplications were implied by NGS and confirmed by MLPA in three patients in our cohort using data-based algorithms[42] and would have been missed by traditional Sanger sequencing.…”

Section: Discussionmentioning

confidence: 86%

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing

Zheng

Jin

et al. 2017

PLoS ONE

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This study aimed to study the diagnostic value of targeted next-generation sequencing (NGS) in limb-girdle muscular dystrophies (LGMDs), and investigate the mutational spectrum of Chinese LGMD patients. We performed targeted NGS covering 420 genes in 180 patients who were consecutively suspected of LGMDs and underwent muscle biopsies from January 2013 to May 2015. The association between genotype and myopathological profiles was analyzed in the genetically confirmed LGMD patients. With targeted NGS, one or more rare variants were detected in 138 patients, of whom 113 had causative mutations, 10 sporadic patients had one pathogenic heterozygous mutation related to a recessive pattern of LGMDs, and 15 had variants of uncertain significance. No disease-causing mutation was found in the remaining 42 patients. Combined with the myopathological findings, we achieved a positive genetic diagnostic rate as 68.3% (123/180). Totally 105 patients were diagnosed as LGMDs with genetic basis. Among these 105 patients, the most common subtypes were LGMD2B in 52 (49.5%), LGMD2A in 26 (24.8%) and LGMD 2D in eight (7.6%), followed by LGMD1B in seven (6.7%), LGMD1E in four (3.8%), LGMD2I in three (2.9%), and LGMD2E, 2F, 2H, 2K, 2L in one patient (1.0%), respectively. Although some characteristic pathological changes may suggest certain LGMD subtypes, both heterogeneous findings in a certain subtype and overlapping presentations among different subtypes were not uncommon. The application of NGS, together with thorough clinical and myopathological evaluation, can substantially improve the molecular diagnostic rate in LGMDs. Confirming the genetic diagnosis in LGMD patients can help improve our understanding of their myopathological changes.

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Section: Discussionmentioning

confidence: 86%

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing

Zheng

Jin

et al. 2017

PLoS ONE

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“…A CNV analysis was performed with NGS data following the previously reported CoNVaDING method, which had been specifically developed for gene panel data at high-coverage and enables accurately single-exon detection 60 . Briefly, it uses the average coverage of each specified target to perform calculations starting from BAM files.…”

Section: Materials/subjects and Methodsmentioning

confidence: 99%

“…Finally, it performs a filtering step that renders the list with deletions and duplications. The method includes QC metrics that make it possible to distinguish high-quality from low-quality samples 60 .…”

Section: Materials/subjects and Methodsmentioning

confidence: 99%

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Sánchez‐Navarro

Silva

Blanco‐Kelly

et al. 2018

Sci Rep

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Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.

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“…CNV analysis of MPS data has resulted in the identification of several novel CNVs [23*, 25, 31, 32*, 49, 54*] and has shown that many genes can harbor CNVs. Comprehensive CNV detection is as important as comprehensive SNV detection and analysis and must be included in all analytic pipelines.…”

Section: Cnv Inclusion and Methodologymentioning

confidence: 99%

“…Comprehensive CNV detection is as important as comprehensive SNV detection and analysis and must be included in all analytic pipelines. Two new CNV detection methods based upon differential read depth have been reported [23*, 54*], which should make CNV incorporation into TGE+MPS workflows more widespread.…”

Section: Cnv Inclusion and Methodologymentioning

confidence: 99%

Navigating genetic diagnostics in patients with hearing loss

Sloan-Heggen

Smith

2016

Current Opinion in Pediatrics

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Purpose of review In the age of targeted genomic enrichment and massively parallel sequencing there is no more efficient genetic testing method for the diagnosis of hereditary hearing loss. More clinical tests are on the market, which can make choosing good tests difficult. Recent findings More and larger comprehensive genetic studies in patients with hearing loss have been published recently. They remind us of the importance of looking for both single nucleotide variation and copy number variation in all genes implicated in non-syndromic hearing loss. They also inform us of how a patient’s history and phenotype provide essential information in the interpretation of genetic data. Summary Choosing the most comprehensive genetic test improves the chances of a genetic diagnosis and thereby impacts clinical care.

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CoNVaDING: Single Exon Variation Detection in Targeted NGS Data

Cited by 80 publications

References 22 publications

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Navigating genetic diagnostics in patients with hearing loss

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