Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data

Khateb, Samer; Hanany, Mor; Khalaileh, Ayat; Beryozkin, Avigail; Meyer, Shirley; Abu-Diab, Alaa; Turky, Fathieh Abu; Mizrahi-Meissonnier, Liliana; Lieberman, Sari; Ben-Yosef, Tamar; Banin, Eyal; Sharon, Dror

doi:10.1136/jmedgenet-2016-103825

Cited by 32 publications

(31 citation statements)

References 32 publications

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“…In conclusion, our rate of discovery for likely solving variants in IRD patients has increased from 55.8% to 65.8% by including information from CNVs and MAK-Alu insertions. This represents a significant improvement in solving genetic cases, consistent with or higher than in previous studies 47,48,[73][74][75] Note that in general, duplications were predicted less often, and were on average larger in size than predicted deletions. D) Comparison of the gCNV predicted sizes of validated CNVs that were also predicted by the SNP array (gCNV SA+ve) versus the gCNV predicted size of validated CNVs that were not predicted by the SA (gCNV SAve).…”

Section: Discussionsupporting

confidence: 87%

“…However, PVs in each new disease gene are rare, affecting a handful of IRD patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] , suggesting that the missing genetic causality largely lies in the known IRD genes. A considerable proportion of these elusive PVs are due to structural variations (SVs) such as copy number variations (CNVs), or deep intronic variants that affect splicing 36,[39][40][41][42][43][44][45][46][47][48][49] , which are not readily available from the standard output of targeted next generation sequencing (NGS) pipelines.…”

Section: Introductionmentioning

confidence: 99%

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Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Zampaglione

Kinde

Place

et al. 2019

Preprint

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Purpose: Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy number variations (CNVs), which we believe are a major contributor to unsolved IRD cases. Methods:Five hundred IRD patients were analyzed with targeted next generation sequencing (NGS). The NGS data was used to detect CNVs with ExomeDepth and gCNV and the results were compared to CNV detection with a SNP-Array. Likely causal CNV predictions were validated by quantitative (q)PCR.Results: Likely disease-causing single nucleotide variants (SNVs) and small indels were found in 55.8% of subjects. PVs in USH2A (11.6%), RPGR (4%) and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy.Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene.Conclusions: CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Zampaglione

Kinde

Place

et al. 2019

Preprint

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“…Structural variants also represent an underestimated mutational burden that contributes to missing heritability and oligogenic mechanisms, not only in non-syndromic RD, but also in BBS and Joubert syndrome 20,24–26,51,52 . Here, we report novel heterozygous multi-exon structural variants for BBS1 and RPGRIP1 that were identified by targeted comparative read-depth analysis.…”

Section: Discussionmentioning

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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“…9,[17][18][19][20]25 Compared to those previous studies, our study possessed two advantages: (1) we were the first to use whole-genome-wide genotyping arrays to dissect the contributions of CNVs in a large cohort of IRD patients; and (2) we analyzed not only the deletions, but also the duplications of genetic materials. However, there were certain limitations in this study as well.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease

Huang

Mao

Huang

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data

Abstract: We performed here a comprehensive analysis of WES data as a tool for identifying large genomic deletions in patients with IRDs. Our analysis indicates that large deletions are relatively frequent (about 10% of our WES cohort) and should be screened when analysing WES data.

Cited by 32 publications

References 32 publications

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

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

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease

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