Benchmark of tools for CNV detection from NGS panel data in a genetic diagnostics context

Moreno-Cabrera, José Marcos; Valle, Jesús Del; Castellanos, Elisabeth; Feliubadaló, Lídia; Pineda, Marta; Brunet, Joan; Serra, Eduard; Capellà, Gabriel; Lázaro, Conxi; Gel, Bernat

doi:10.1101/850958

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…In fact, benchmarking of several CNVs detection tools from exome data showed that a significant fraction of called CNVs are only present in a single tool [ 76 ]. It was demonstrated also that ExomeDepth is one the most balanced tools concerning sensitivity and specificity [ 77 ] and this latter was supported to be integrated with routine targeted NGS diagnostic services for Mendelian diseases [ 78 ]. Additionally, clinically relevant CNVs resulting from the different breast cancer studies highly depend on the bioinformatic tools and the methodology used to prioritize variants and to interpret results.…”

Section: Discussionmentioning

confidence: 99%

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

et al. 2021

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Hereditary breast cancer accounts for 5–10% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in BRCA1/2 genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9 BRCA negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes.

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Section: Discussionmentioning

confidence: 99%

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

et al. 2021

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“…such as read depth analysis, paired-end mapping, or split read approach (43). Therefore, both SNVs and CNVs can be identified by NGS.…”

Section: Discussionmentioning

confidence: 99%

Mutation spectrum and frequency of copy number variations of the ANOS1 gene in patients with Kallmann syndrome or normosmic isolated hypogonadotropic hypogonadism

Kim

Choi

Hwang

et al. 2023

Endocrine Connections

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Objective: This study was performed to investigate the molecular characteristics and frequency of copy number variations (CNVs) of ANOS1 in patients with Kallmann syndrome (KS) or normosmic isolated hypogonadotropic hypogonadism (nIHH) using multiplex ligation-dependent probe amplification (MLPA) analysis and sequencing. Methods: Among 45 patients from 43 independent families, Sanger sequencing, next-generation sequencing (NGS), or microarray was performed in 24 patients from 23 families, and MLPA was performed in 19 patients who did not show rare sequence variants (n = 18) or ANOS1 amplification by PCR (n = 1). Results: Seven patients (4 patients with KS, 1 patient with nIHH, one prepubertal boy with anosmia, and one newborn patient) from 6 families (6/43, 14%) harbored molecular defects in ANOS1 including a nonsense mutation [c.1140G>A (p.W380*)], a frameshift mutation [c.1260del (p.Q421Kfs*61)], a splice site mutation (c.1449+1G>A), an exon 7 deletion, a complete deletion, and 7.9 Mb-sized inversion encompassing ANOS1. The complete deletion of ANOS1 was identified in a neonate with a micropenis and cryptorchidism. Unilateral renal agenesis was found in three patients, whereas only one patient displayed both synkinesia and sensorineural hearing loss. There was no reversal of hypogonadotropic hypogonadism in any patient during 9.1 ± 2.9 years of treatment with testosterone enanthate. Conclusions: Molecular defects in the ANOS1 gene could be identified in 14% of probands including various types of CNVs (3/43, 7.0%). Comprehensive analysis using sequencing and analysis for CNVs is required to detect molecular defects in ANOS1.

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“…Nine out of sixteen disease-causing deletions only involved one to two exons (Table 1). With targeted NGS and CMA, the CNVs with small size are more likely to be missed (6,55,56). Our data showed that small CNVs affecting less than three exons can account for a significant portion of CNVs, and WGS can detect many of them with its unique combination of coverage depth and breakpoint detection.…”

Section: Only Pathogenic and Likely Pathogenic Deletions Were Identif...mentioning

confidence: 99%

“…However, because most CMA probes target the exons, when breakpoints are present in the introns or the intragenic regions, the identification of breakpoint location is much more difficult. Targeted-NGS-based CNV detection is becoming increasingly prevalent in recent years, however, they also pose similar weaknesses as CMA: the resolution is usually limited to two or more-consecutive exons, and the breakpoints cannot be mapped when they are located in non-targeted regions (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Systematic assessment of the contribution of structural variants to inherited retinal diseases

Wen

Wang

Qian

et al. 2023

Preprint

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Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads, and discordant read pairs. PCR followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. In total, sixteen candidate pathogenic SVs were identified in sixteen families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive, and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS, PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.

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Benchmark of tools for CNV detection from NGS panel data in a genetic diagnostics context

Cited by 4 publications

References 30 publications

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

Mutation spectrum and frequency of copy number variations of the ANOS1 gene in patients with Kallmann syndrome or normosmic isolated hypogonadotropic hypogonadism

Systematic assessment of the contribution of structural variants to inherited retinal diseases

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