AnnotSV: an integrated tool for structural variations annotation

Geoffroy, Véronique; Herenger, Yvan; Kress, Arnaud; Stoetzel, Corinne; Piton, Amélie; Dollfus, Hélène; Muller, Jean

doi:10.1093/bioinformatics/bty304

Cited by 308 publications

(273 citation statements)

References 11 publications

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“…Our analysis was focused on compound heterozygous and homozygous variants (SNV/indel/SV) consistent with a recessive mode of transmission. Structural variants were predicted using by default the CANOES program (Backenroth et al., ) and annotated thanks to our in house script AnnotSV (Geoffroy et al., ) based on the classical annotations such as the Database of Genomic Variants (DGV) (MacDonald, Ziman, Yuen, Feuk, & Scherer, ). The IFT140 nomenclature is based on the accession number NM_014714.3 from the RefSeq database (O'Leary et al., ).…”

Section: Methodsmentioning

confidence: 99%

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

et al. 2018

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Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.

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Section: Methodsmentioning

confidence: 99%

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

et al. 2018

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“…Very stringent filtering criteria were applied to filter out nonpathogenic variants (Table S1): (a) Variants represented with an allele frequency >1% in public variation databases including the 1000Genomes (Auton et al, ), the genome aggregation database (gnomAD; Lek et al, ), the database of genomic variants (MacDonald, Ziman, Yuen, Feuk, & Scherer, ), or our internal exome database, and (b) variants in 5′ and 3′ untranslated region, downstream, upstream, intronic, and synonymous locations without pathogenic prediction of local splice effect. Structural variants (SVs) were predicted using CANOES (Backenroth et al, ) and annotated by AnnotSV 2.0 (Geoffroy, Herenger et al, ). Our analysis considered all inheritance modes but given that two families were consanguineous, we focused on compound heterozygous and homozygous variants consistent with a recessive transmission.…”

Section: Methodsmentioning

confidence: 99%

NovelIQCEvariations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

et al. 2019

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Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high‐genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole‐exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients’ fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

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“…Longer deletions of length >= 100bp were identified using SvABA, and the resulting VCF was annotated using svaba-annotate.R and AnnotSV version 1.2. 20 Long deletions identified in BRCA1 and BRCA2 were checked for validity and impact to the reading frame via manual inspection of the raw reads (*.alignments.txt.gz) aligned to contigs assembled by SvABA.…”

Section: Methodsmentioning

confidence: 99%

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy inBRCA1/2-mutant metastatic breast cancer

Waks

Cohen

Kochupurakkal

et al. 2019

Preprint

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Running head: Mechanisms of resistance to PARP inhibitors/platinum in metastatic breast cancer Keywords: BRCA1, BRCA2, breast cancer, PARP inhibitor, platinum Key message: We analyzed mechanisms of resistance to PARP inhibitor or platinum chemotherapy in 8 patients with BRCA1/2-mutant metastatic breast cancer. Four patients acquired resistance by genomic reversion to a functional BRCA1/2 protein; two patients acquired resistance by upregulating DNA end resection. RAD51 foci by immunohistochemistry correlated with clinical response to PARP inhibitor/platinum. Abstract Background:Little is known about mechanisms of resistance to PARP inhibitors and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. Patients and Methods:We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARP inhibitor or platinum chemotherapy. Whole exome sequencing was performed on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was performed for functional assessment of intact homologous recombination. Results:Pre-and post-resistance tumor samples were sequenced from 8 patients (4 with BRCA1 and 4 with BRCA2 mutation; 4 treated with PARP inhibitor and 4 with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore homologous recombination through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of homologous recombination. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy.Conclusions: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in 4 of 8 patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

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AnnotSV: an integrated tool for structural variations annotation

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 308 publications

References 11 publications

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

NovelIQCEvariations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy inBRCA1/2-mutant metastatic breast cancer

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