Detection of CNVs in NGS Data Using VS-CNV

Fortier, Nathan; Rudy, Gabe; Scherer, Andreas

doi:10.1007/978-1-4939-8666-8_9

Cited by 12 publications

(8 citation statements)

References 24 publications

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“…Copy number variations (CNV) were detected using VarSeq™ v2.1 (VS‐CNV), which analyzes changes in WES coverage between the sample and controls (Fortier et al, 2018 ), and the detected CNVs were visually evaluated using GenomeBrowse® (Golden Helix, Inc.; Golden Helix, 2018a , 2018b ). Homozygous or heterozygous deletions were filtered based on p‐values (< 0.001) and annotated using ClinVar (Landrum et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

The causes of Fanconi anemia in South Asia and the Middle East: A case series and review of the literature

Thompson

Saba

McReynolds

et al. 2021

Molec Gen & Gen Med

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Background Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with characteristic dysmorphology primarily caused by biallelic pathogenic germline variants in any of 22 different DNA repair genes. There are limited data on the specific molecular causes of FA in different ethnic groups. Methods We performed exome sequencing and copy number variant analyses on 19 patients with FA from 17 families undergoing hematopoietic cell transplantation evaluation in Pakistan. The scientific literature was reviewed, and we curated germline variants reported in patients with FA from South Asia and the Middle East. Results The genetic causes of FA were identified in 14 of the 17 families: seven FANCA, two FANCC, one FANCF, two FANCG, and two FANCL. Homozygous and compound heterozygous variants were present in 12 and two families, respectively. Nine families carried variants previously reported as pathogenic, including two families with the South Asian FANCL founder variant. We also identified five novel likely deleterious variants in FANCA, FANCF, and FANCG in affected patients. Conclusions Our study supports the importance of determining the genomic landscape of FA in diverse populations, in order to improve understanding of FA etiology and assist in the counseling of families.

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Section: Methodsmentioning

confidence: 99%

The causes of Fanconi anemia in South Asia and the Middle East: A case series and review of the literature

Thompson

Saba

McReynolds

et al. 2021

Molec Gen & Gen Med

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“…There are several programs to identify CNV from NGS data. However, there was no difference in detection when compared with the eXome Hidden Markov Model, which is the one typically used (data not shown) . In CES, the genes to be examined are limited; therefore, it is possible that there are CNV that could not be detected.…”

Section: Discussionmentioning

confidence: 97%

An efficient genetic test flow for multiple congenital anomalies and intellectual disability

Yokoi

Enomoto

Tsurusaki

et al. 2020

Pediatrics International

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Background: Genetic testing has enabled the diagnosis of multiple congenital anomalies and/or intellectual disabilities. However, because of the phenotypic variability in these disorders, selection of an appropriate genetic test can be difficult and complex. For clinical examination, particularly in clinical facilities, a simple and standardized system is needed. Methods: We compared microarray comparative genomic hybridization and clinical exome sequencing with regard to diagnostic yield, cost, and time required to reach a definitive diagnosis. After first performing G-banding for 200 patients with multiple congenital anomalies and/or intellectual disability, as a subsequent genetic test, microarray and clinical exome sequencing were compared with regard to diagnostic yield, cost, and time required.Results: There was no obvious difference in the diagnostic rate between the two methods; however, clinical exome sequencing was superior in terms of cost and time. In addition, clinical exome sequencing could sufficiently identify copy number variants, and even smaller copy number variants could be identified.Conclusions: Clinical exome sequencing should be implemented earlier as a genetic test for undiagnosed patients with multiple congenital anomalies and/or intellectual disabilities. Our results can be used to establish inspection methods in clinical facilities.

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“…HNF1B copy number loss were called from a referenced-based CLAMMS algorithm using exome sequencing (24), and confirmed by Illumina chip array. Samples underwent quality assurance including removal of samples of sex mismatch, other large chromosomal abnormalities, and outliers of derivative log ratio spread (DLRS) and genomic wave factors (25). Outliers were defined as 1.5 times the interquartile range (IQR) from the third quartile of the distribution of DLRS.…”

Section: Variant Annotation and Classificationmentioning

confidence: 99%

Framework for prioritizing variants of unknown significance from clinical genetic testing in kidney disease – utility of multidisciplinary approach to gather evidence of pathogenicity for Hepatocyte Nuclear Factor-1β (HNF1B) p.Arg303His

Mirshahi

Bhan

Tholen

et al. 2022

Preprint

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Monogenic causes in over 300 kidney-associated genes account for roughly 12% of end stage kidney disease (ESKD) cases. Advances in next generation sequencing, and large customized panels enable the diagnosis of monogenic kidney disease noninvasively at relatively low cost, allowing for more precise management for patients and their families. A major challenge is interpreting rare variants, many of which are classified as variants of unknown significance (VUS). We present a framework in which we thoroughly evaluated and provided evidence of pathogenicity for HNF1B-p.Arg303His, a VUS returned from clinical genetic testing for a kidney transplant candidate. This blueprint, designed by a multi-disciplinary team of clinicians, molecular biologists, and diagnostic geneticists, includes using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS carriers, examination of existing genetic databases, as well as functional testing. With our approach, we demonstrate evidence for pathogenicity for HNF1B-p.Arg303His by showing similar burden of kidney manifestations in this variant to known HNF1B pathogenic variants, and greater burden compared to non-carriers. Determination of a molecular diagnosis for the example family allows for proper surveillance and management of HNF1B-related manifestations such as kidney disease, diabetes, and hypomagnesemia with important implications for safe living-related kidney donation. The candidate gene-variant pair also allows for clinical biomarker testing for aberrations of linked pathways. This working model may be applicable other diseases of genetic etiology.

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Detection of CNVs in NGS Data Using VS-CNV

Cited by 12 publications

References 24 publications

The causes of Fanconi anemia in South Asia and the Middle East: A case series and review of the literature

The causes of Fanconi anemia in South Asia and the Middle East: A case series and review of the literature

An efficient genetic test flow for multiple congenital anomalies and intellectual disability

Framework for prioritizing variants of unknown significance from clinical genetic testing in kidney disease – utility of multidisciplinary approach to gather evidence of pathogenicity for Hepatocyte Nuclear Factor-1β (HNF1B) p.Arg303His

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