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

Nishiguchi K.M.; Tearle R.G.; Liu Y.P.Oh E.C.Miyake N.Benaglio P.Harper S.Koskiniemi-Kuendig H.Venturini G.Sharon D.Koenekoop R.K.Nakamura M.Kondo M.Ueno S.Yasuma T.R.Beckmann J.S.Ikegawa S.Matsumoto N.Terasaki H.Berson E.L.Katsanis N.Rivolta C.

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第40期|16139-16144|共6页
作者
Nishiguchi K.M.; Tearle R.G.; Liu Y.P.Oh E.C.Miyake N.Benaglio P.Harper S.Koskiniemi-Kuendig H.Venturini G.Sharon D.Koenekoop R.K.Nakamura M.Kondo M.Ueno S.Yasuma T.R.Beckmann J.S.Ikegawa S.Matsumoto N.Terasaki H.Berson E.L.Katsanis N.Rivolta C.;
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作者单位

McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, QC H3H 1P3, Canada;

Department of Ophthalmology, Nagoya University School of Medicine, Nagoya 466-8550, Japan;

Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo 108-8639, JapanDepartment of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama 236-0004, JapanBerman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, United StatesCenter for Human Disease Modeling, Duke University, Durham, NC 27710, United StatesDepartment of Medical Genetics, University of Lausanne, 1005 Lausanne, SwitzerlandComplete Genomics, Inc., Mountain View, CA 94043, United StatesDepartment of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Ciliopathy; Medical genetics; Ophthalmology; Retinal blindness;

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

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