High-Resolution Homozygosity Mapping Is a Powerful Tool to Detect Novel Mutations Causative of Autosomal Recessive RP in the Dutch Population

被引:60
作者
Collin, Rob W. J. [1 ,2 ,3 ]
van den Born, L. Ingeborgh [4 ]
Klevering, B. Jeroen [2 ]
de Castro-Miro, Marta [1 ]
Littink, Karin W. [1 ,4 ]
Arimadyo, Kentar [1 ]
Azam, Maleeha [1 ,5 ]
Yazar, Volkan [1 ]
Zonneveld, Marijke N. [1 ]
Paun, Codrut C. [1 ]
Siemiatkowska, Anna M. [1 ]
Strom, Tim M. [6 ]
Hehir-Kwa, Jayne Y. [1 ,3 ]
Kroes, Hester Y. [7 ]
de Faber, Jan-Tjeerd H. N. [4 ]
van Schooneveld, Mary J. [8 ,9 ]
Heckenlively, John R. [10 ]
Hoyng, Carel B. [2 ]
den Hollander, Anneke I. [1 ,2 ,3 ]
Cremers, Frans P. M. [1 ,3 ,5 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 GA Nijmegen, Netherlands
[3] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 GA Nijmegen, Netherlands
[4] Rotterdam Eye Hosp, Rotterdam, Netherlands
[5] Inst Informat Technol, COMSATS Commiss Sci & Technol Sustainable Dev S, Dept Biosci, Islamabad, Pakistan
[6] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany
[7] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands
[8] Netherlands Inst Neurosci, Amsterdam, Netherlands
[9] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands
[10] Univ Michigan, Kellogg Eye Ctr, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA
关键词
RETINALDEHYDE-BINDING PROTEIN; LEBER CONGENITAL AMAUROSIS; NUCLEAR RECEPTOR GENE; CONE-ROD DYSTROPHY; RETINITIS-PIGMENTOSA; ALPHA-SUBUNIT; RDH12; MUTATIONS; EYS GENE; IDENTIFICATION; PHOSPHODIESTERASE;
D O I
10.1167/iovs.10-6185
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
PURPOSE. To determine the genetic defects underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch population and in a subset of patients originating from other countries. The hypothesis was that, because there has been little migration over the past centuries in certain areas of The Netherlands, a significant fraction of Dutch arRP patients carry their genetic defect in the homozygous state. METHODS. High-resolution genome-wide SNP genotyping on SNP arrays and subsequent homozygosity mapping were performed in a large cohort of 186 mainly nonconsanguineous arRP families living in The Netherlands. Candidate genes residing in homozygous regions were sequenced. RESULTS. In similar to 94% of the affected individuals, large homozygous sequences were identified in their genome. In 42 probands, at least one of these homozygous regions contained one of the 26 known arRP genes. Sequence analysis of the corresponding genes in each of these patients revealed 21 mutations and two possible pathogenic changes, 14 of which were novel. All mutations were identified in only a single family, illustrating the genetic diversity within the Dutch population. CONCLUSIONS. This report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity. (Invest Ophthalmol Vis Sci. 2011;52:2227-2239) DOI:10.1167/iovs.10-6185
引用
收藏
页码:2227 / 2239
页数:13
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