Copy-Number Variations in<i>EYS:</i>A Significant Event in the Appearance of arRP

Pieras, Juan Ignacio; Barragán, Isabel; Borrego, Salud; Audo, Isabelle; Pozo, María González del; Bernal, Sara; Baiget, Montserrat; Zeitz, Christina; Bhattacharya, Shom Shanker; Antiñolo, Guillermo

doi:10.1167/iovs.11-7292

Cited by 41 publications

(43 citation statements)

References 15 publications

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“…We found that one of the pathogenic EYS alleles was a large SV (446 kb) with a complex genomic rearrangement. This finding supports the notion that SVs represent frequent pathogenic mutations in this gene (17). A homozygous nonsense mutation in exon 6 of DFNB31 was identified in R18, a patient with nonsyndromic ARRP.…”

Section: Discussionsupporting

confidence: 86%

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Nishiguchi

Tearle

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

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We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonineprotein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome. medical genetics | ophthalmology | ciliopathy | retinal blindness

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Section: Discussionsupporting

confidence: 86%

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Nishiguchi

Tearle

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

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“…This is in line with our findings, as bioinformatic analysis of the breakpoint regions suggests nonhomologous end joining or fork stalling and template switching as the most likely mechanisms for this novel deletion (data not shown). Although only a limited number of CNVs have been described in RDs, not surprisingly with low frequencies comparable to other single-base RD mutations, 26,36 their occurrence warrants implementation of a CNV analysis algorithm in addition to IBD data analysis.…”

Section: Discussionmentioning

confidence: 99%

“…25 Subsequent Sanger sequencing of exons with a coverage below 20× did not identify a second mutation. As several copy-number variations (CNV) have been described in EYS, 26 multiplex ligation-dependent probe amplification was performed. However, no CNV was detected.…”

Section: Combined Ibd Mapping and Wesmentioning

confidence: 99%

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

Coppieters

Schil

Bauwens

et al. 2014

Genetics in Medicine

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“…2006; Pieras et al. 2011). It is widely accepted that CNVs, especially deletion alleles, often result in affected phenotypes or increase an individual's susceptibility for the disease (Feuk et al.…”

Section: Introductionmentioning

confidence: 99%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole‐exome sequencing (WES) and whole‐genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37‐bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled‐coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult‐onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis‐regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss‐of‐function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu‐mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu‐mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease.

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Copy-Number Variations inEYS:A Significant Event in the Appearance of arRP

Cited by 41 publications

References 15 publications

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

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