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Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families with Leber Congenital Amaurosis

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Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families with Leber Congenital Amaurosis Genetics Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families With Leber Congenital Amaurosis Yabin Chen,1 Qingyan Zhang,2 Tao Shen,1 Xueshan Xiao,1 Shiqiang Li,1 Liping Guan,2 Jianguo Zhang,2 Zhihong Zhu,2 Ye Yin,2 Panfeng Wang,1 Xiangming Guo,1 Jun Wang,2 and Qingjiong Zhang1 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China 2BGI-Shenzhen, Shenzhen, China Correspondence: Qingjiong Zhang, PURPOSE. Leber congenital amaurosis (LCA) is a genetically heterogeneous disease with, to State Key Laboratory of Ophthal- date, 19 identified causative genes. Our aim was to evaluate the mutations in all 19 genes in mology, Zhongshan Ophthalmic Chinese families with LCA. Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, METHODS. LCA patients from 41 unrelated Chinese families were enrolled, including 25 China; previously unanalyzed families and 16 families screened previously by Sanger sequencing, but [email protected]. with no identified mutations. Genetic variations were screened by whole-exome sequencing YC, QZ, JW, and QZ contributed and then validated using Sanger sequencing. equally to the work presented here RESULTS. A total of 41 variants predicted to affect protein coding or splicing was detected by and should therefore be regarded as whole-exome sequencing, and 40 were confirmed by Sanger sequencing. Bioinformatic and equivalent authors. segregation analyses revealed 22 potentially pathogenic variants (17 novel) in 15 probands, Submitted: January 4, 2013 comprised of 3 of 16 previously analyzed families and 12 of 25 (48%) previously unanalyzed Accepted: April 29, 2013 families. In the latter 12 families, mutations were found in CEP290 (three probands); Citation: Chen Y, Zhang Q, Shen T, et GUCY2D (two probands); and CRB1, CRX, RPE65, IQCB1, LCA5, TULP1, and IMPDH1 (one al. Comprehensive mutation analysis proband each). Based on the results from 87 previously analyzed probands and 25 new cases, by whole-exome sequencing in 41 GUCY2D, CRB1, RPGRIP1, CEP290, and CRX were the five most frequently mutated genes, Chinese families with Leber congeni- which was similar to the results from studies in Caucasian subjects. tal amaurosis. Invest Ophthalmol Vis Sci. 2013;54:4351–4357. CONCLUSIONS. Whole-exome sequencing detected mutations in the 19 known LCA genes in DOI:10.1167/iovs.13-11606 approximately half of Chinese families with LCA. These results, together with our previous results, demonstrate the spectrum and frequency of mutations of the 19 genes responsible for LCA in Han Chinese individuals. Whole-exome sequencing is an efficient method for detecting mutations in highly heterogeneous hereditary diseases. Keywords: Leber congenital amaurosis, exome sequencing, mutation screening, genotype- phenotype, Chinese Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 4351 Downloaded from jov.arvojournals.org on 10/02/2021 Mutation Analysis in Leber Congenital Amaurosis IOVS j June 2013 j Vol. 54 j No. 6 j 4352 eber congenital amaurosis (LCA, MIM 204000) is the most male and 12 were female; 34 were isolated cases, while six Lsevere form of inherited retinal dystrophy, with an showed autosomal-recessive inheritance, and one showed estimated prevalence of 1:81,0001 to 1:30,000.2 This condition autosomal-dominant inheritance. Written informed consent accounts for more than 5% of all retinal dystrophies and conforming to the tenets of the Declaration of Helsinki was approximately 20% of children attending schools for the blind.3 obtained from the participants or their guardians before the LCA is inherited most frequently as an autosomal-recessive study. This study was approved by the Institutional Review trait, but also may be transmitted as an autosomal-dominant Board of the Zhongshan Ophthalmic Center. Genomic DNA trait in rare cases.4 Clinical features of LCA include profound was extracted from leukocytes of a peripheral blood sample of loss of visual function at birth or within the first year of life, each participant as described previously.37 nystagmus, oculodigital sign of Franceschetti, sluggish pupil- lary light reflex, and variable fundus changes ranging from Whole-Exome Sequencing relatively normal appearance to severe pigmentary degenera- Whole-exome sequencing was performed through a commercial tion. Markedly reduced or no identifiable rod and cone service from BGI Shenzhen (Shenzhen, China; available in the responses on electroretinogram recording in infancy are the public domain at http://www.genomics.cn/index). The methods 5 hallmark of LCA. for exome capture, exon-enriched DNA library construction, To date, mutations in at least 19 genes have been identified 6 sequencing, genotyping, and variant analysis have been reported as responsible for LCA: guanylate cyclase 2D (GUCY2D), previously.38 In brief, a NimbleGen SeqCap EZ Exome (44M; retinal pigment epithelium-specific protein 65 kDa (RPE65),7 8 Roche, Basil, Switzerland) array was used to perform the exome spermatogenesis-associated protein 7 (SPATA7), aryl hydro- capture. Subsequently, exon-enriched DNA fragments were carbon-interacting receptor protein-like 1 (AIPL1),9 Leber 10 loaded on the Illumina Genome Analyzer II (Illumina, Santiago, congenital amaurosis 5 gene (LCA5), retinitis pigmentosa CA) platform for sequencing. The mean exome coverage was set (RP) GTPase regulator-interacting protein (RPGRIP1),11 cone- 12 as 60-fold. For variant analysis, alignment of the sequencing rod homeobox-containing gene (CRX), crumbs homolog 1 reads with UCSC hg19 was performed on a SOAPaligner.39,40 (Drosophila)(CRB1),13 centrosomal protein 290 kDa 14 0 SOAPsnp was used to calculate the likelihood of possible (CEP290), inosine 5 -monophosphate dehydrogenase type genotypes in target regions.41 Variants in all 19 LCA-related 1(IMPDH1),15 retinal degeneration 3 (RD3),16 retinol dehy- 17 genes detected by whole-exome sequencing were selected for drogenase 12 (RDH12), lecithin retinol acyltransferase further verification. (LRAT),18 tubby-like protein 1 (TULP1),19 inwardly rectifying potassium channel Kir7.1 (KCNJ13),20 calcium-binding protein Sanger Sequencing 4(CABP4),21 IQ motif-containing protein B1 (IQCB1),22 orthodenticle homolog 2 (OTX2),23 and nicotinamide nucleo- Sanger sequencing was used to validate the variants found in tide adenylyltransferase 1 (NMNAT1).24 Mutations in most of whole-exome sequencing in the 19 genes. Segregation analyses the genes above are associated with autosomal-recessive LCA, were performed in patients with available relatives. Genomic whereas mutations in CRX,4 IMPDH1,15 and OTX223 usually information about the 19 genes is listed in Supplementary Table are associated with autosomal-dominant LCA. Studies of these S1. Primers used to amplify fragments harboring individual genes, based on an individual gene or a subset of genes, have variants were designed by Primer3 (available in the public identified numerous mutations.25–31 However, to our knowl- domain at http://frodo.wi.mit.edu/primer3/), and the sequenc- edge no systematic analysis of these 19 genes to evaluate the es of these primers are listed in Supplementary Table S2. full spectrum of variations in patients with LCA has been Additionally, a known mutation hot spot outside the capture reported. Exon-by-exon analysis of the 19 genes by conven- range of the exome array, c.2991 þ 1665A > GinCEP290, was tional Sanger sequencing is not suitable for mutation detection analyzed by direct Sanger sequencing in all probands. in a clinical setting, as it is labor- and time-intensive.32 Polymerase chain reaction was used to amplify the genomic Therefore, fast and reliable new techniques are needed to fragments with variants, and the sequences of the amplicons detect mutations in this disease. An LCA mutation chip (Asper were determined by Sanger sequencing using a BigDye Ophthalmics; Asper Biotech Ltd., Tartu, Estonia) was devel- Terminator cycle sequencing kit v3.1 and an ABI 3130 Genetic oped that detects all known mutations identified in LCA, but Analyzer (both from Applied Biosystems, Foster City, CA). The cannot detect novel mutations.33 A SNP-chip for LCA diagnosis resultant sequences were compared to consensus sequences may be used in patients with a family history, but most LCA using Seqman software (Lasergene 8.0; DNASTAR, Inc., cases are isolated patients born to unaffected parents.34 Madison, WI). The possible impact of amino acid substitutions Recently, with the rapid development of next-generation was predicted by SIFT (available in the public domain at http:// sequencing, whole-exome sequencing has arisen as an sift.jcvi.org/) and PolyPhen-2 (available in the public domain at 42 impressive tool for mutation screening, especially for highly http://genetics.bwh.harvard.edu/pph2/). Splice site predic- heterogeneous hereditary diseases.35 In our study, whole- tion by a neural network was used to predict the effects of exome sequencing was used to detect variants in 41 unrelated variants on splicing sites (available in the public domain at Chinese patients with LCA. Variants found in the 19 LCA- http://www.fruitfly.org/seq_tools/splice.html).43 Base-by-base related genes were verified by Sanger sequencing. conservation scores ranging from 0 to 1, with higher scores indicating the higher degrees of conservation, were obtained using PhastCons (available in the public domain at http:// MATERIALS AND METHODS varianttools.sourceforge.net/Annotation/PhastCons).44
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