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Genotype–Phenotype Correlation and Mutation Spectrum in a Large Cohort of Patients with Inherited Retinal Dystrophy Revealed by Next-Generation Sequencing

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Genotype–Phenotype Correlation and Mutation Spectrum in a Large Cohort of Patients with Inherited Retinal Dystrophy Revealed by Next-Generation Sequencing © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Open Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing Xiu-Feng Huang, MB1, Fang Huang, MD1, Kun-Chao Wu, MD1, Juan Wu, MD1, Jie Chen, MD, PhD1, Chi-Pui Pang, PhD2, Fan Lu, MD, OD1, Jia Qu, MD1 and Zi-Bing Jin, MD, PhD1 Purpose: Inherited retinal dystrophy (IRD) is a leading cause of correlations were discovered, and phenotypic trends noted. Three blindness worldwide. Because of extreme genetic heterogeneity, cases are reported, including the identification of AHI1 as a novel the etiology and genotypic spectrum of IRD have not been clearly candidate gene for nonsyndromic retinitis pigmentosa. defined, and there is limited information on genotype–phenotype Conclusion: This study revealed novel genotype–phenotype corre- correlations. The purpose of this study was to elucidate the muta- lations, including a novel candidate gene, and identified 124 genetic tional spectrum and genotype–phenotype correlations of IRD. defects within a cohort with IRD . The identification of novel geno- Methods: We developed a targeted panel of 164 known retinal dis- type–phenotype correlations and the spectrum of mutations greatly ease genes, 88 candidate genes, and 32 retina-abundant microRNAs, enhance the current knowledge of IRD phenotypic and genotypic used for exome sequencing. A total of 179 Chinese families with IRD heterogeneity, which will assist both clinical diagnoses and personal- were recruited. ized treatments of IRD patients. Genet Med advance online publication 6 November 2014 Results: In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel muta- Key Words: exome sequencing; genotype–phenotype correlations; tions (detection rate, 55.3%). Moreover, novel genotype–phenotype novel mutations; retinal dystrophy INTRODUCTION patients with Leber congenital amaurosis and juvenile RP, iden- Inherited retinal dystrophy (IRD) is a class of monogenic, tifying a genetic predisposition in 40.2% (72/179) of the cases.8 vision-impairing disorders that are caused by retinal degen- Further verifying this approach, Chen et al. used targeted eration. IRD includes retinitis pigmentosa (RP) and allied sequencing of 189 genes in members of 41 Chinese families diseases. The common manifestation is a pathological change with IRD and identified mutations occurring in 14 families.9 in rod and/or cone photoreceptor cells, which are the special- In pilot studies, we successfully performed molecular diagnoses ized and light-sensitive neurons in the retina.1 More than 200 in patients with Usher syndrome and Bardet–Biedl syndrome disease-causing genes associated with IRD have been identi- by assessing a panel of 144 known genes.7,10 Despite success in fied (RetNet, https://sph.uth.edu/retnet/), demonstrating the previous studies, there is still a large proportion of patients with extreme genetic heterogeneity of the disease and therefore IRD who have unidentified genetic mutations.2 In addition, making molecular diagnosis technically challenging, because it there are few thorough studies of the relationship between spe- entails the commitment of substantial time and resources.2 cific genotypes and phenotypes. Next-generation sequencing (NGS) is a powerful new Because NGS allows for the screening of limited networked approach that enables the simultaneous screening of multiple genes in addition to genes known to be associated with the onset genes; it has quickly come to be used extensively in molecular of IRD, targeted exome sequencing of additional candidate diagnosis by sequencing the exome.3–5 Notably, this approach genes is a rapid and cost-effective method of revealing novel has been used for the development of next-generation molecu- disease-causing genes.9,10 Many novel or unrecognized genes lar diagnosis of hereditary eye disorders.6–8 Abu-Safieh and col- interact with known targets of IRD.12,13 In addition, variations leagues6 designed an autozygome-guided screening panel in in microRNA (miRNA) expression could lead to a significant which they were able to successfully identify IRD in patients abnormality in the retina.14 Taken together, this information with six novel candidate genes. In another study, 163 known suggests that networked genes and miRNAs potentially interact IRD genes were screened for by exome sequencing in 179 with key IRD genes, possibly inducing a disease state. 1The Eye Hospital of Wenzhou Medical University, State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, China; 2Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China. Correspondence: Zi-Bing Jin ([email protected]) or Jia Qu ([email protected]) Submitted 19 June 2014; accepted 19 September 2014; advance online publication 6 November 2014. doi:10.1038/gim.2014.138 GEnEticS in mEdicinE | Volume 17 | Number 4 | April 2015 271 ORIGINAL RESEARCH ARTICLE HUANG et al | Inherited retinal dystrophy revealed by next-generation sequencing In this study, we developed a panel of 164 known genes caus- program (http://soap.genomics.org.cn/). Single-nucleotide ing retinal disease, 88 possible candidate genes, and 32 retinal polymorphisms were initially identified by the SOAPsnp pro- miRNAs for genomic DNA capture. This panel was used in gram (http://soap.genomics.org.cn/) after filtering polymerase NGS of the exomes of 179 unrelated patients with IRD. We dis- chain reaction duplicates using SAMtools (http://samtools. covered 124 pathological mutations in 99 patients, including 79 sourceforge.net/). Insertions or deletions were analyzed using novel mutations in previously identified IRD genes. Moreover, BWA (http://bio-bwa.sourceforge.net/) and GATK programs several genotype–phenotype correlations were uncovered, (https://www.broadinstitute.org/gatk/) and then were extracted including identification of AHI1 as a novel candidate gene for using the 1000 Genome, dbSNP135, and HapMap databases, nonsyndromic RP. The identification of novel genotype–phe- as well as an in-house database of 500 exomes. Sequence vari- notype correlations and the mutation spectrum not only greatly ants were standardized according to Human Genome Variant enhance knowledge of IRD phenotypic and genotypic hetero- Society variation nomenclature (http://www.hgvs.org/mut- geneity but also will assist in both the clinical diagnosis and the nomen/) and checked using the Mutalyzer program (http:// development of personalized treatments for IRD. www.lovd.nl/mutalyzer/). Missense variants were assessed with PolyPhen-2 and SIFT, as described previously.19 The splice-site MATERIALS AND METHODS effect was predicted using the BDGP (http://www.fruitfly.org/ Study subjects seq_tools/splice.html) and ASSP programs (http://wangcom- The study protocol was designed in accordance with the tenets puting.com/assp/index.html). of the Declaration of Helsinki and approved by the Ethics Committee of the Eye Hospital of Wenzhou Medical University. Sanger sequencing validation and cosegregation analysis A group of 179 Chinese patients diagnosed with IRD by retina All of the candidate mutations were confirmed by direct Sanger specialists were recruited for this study. Informed consent was sequencing using an ABI 3500 Genetic Analyzer (Applied obtained from all participants. Patients’ initial symptoms and Biosystems, Carlsbad, CA). Variants, including nonsense or complaints included poor vision or night blindness during their frameshift mutations, were considered mutation candidates, first or second decade of life. All patients received a clinical expanding the validation that was performed within kinships diagnosis based on clinical eye examinations. A detailed fam- to analyze cosegregation. ily history was obtained from the probands and/or their rela- tives. Peripheral blood samples were collected from the affected RESULTS patients as well as from unaffected relatives. Patients with IRD The study group included 127 isolated cases (70.9%) and 34 Design of targeted capture panel autosomal recessive cases (19.0%); the remaining 18 cases We developed a panel for targeted DNA capture and sequenc- (10.1%) were either autosomal dominant (n = 12) or X-linked ing by selecting 164 known IRD-related genes from RetNet (n = 6). Diagnoses of participating subjects included RP, cone– and OMIM (Supplementary Table S1 online). The panel also rod dystrophy, Leber congenital amaurosis, Stargardt disease, included a cluster of 88 possible candidate genes with expres- congenital stationary night blindness, Bietti crystalline dystro- sion patterns that were spatiotemporally related to retinal devel- phy, and Usher syndrome (Supplementary Table S4 online). opment15,16 (Supplementary Table S2 online) and 32 abundant retinal miRNAs17,18 (Supplementary Table S3 online). The tar- Exome sequencing of paneled genes geted capture panel included a total of 252 genes, which com- The genomic DNA derived from the 179 patients with IRD was prised 3,376 exons and 615,029-nt coding regions. The panel subjected to massive parallel NGS, which covered a panel of 252 was constructed using the GenCap custom enrichment kit genes and 32 miRNA regions. On average, the mean coverage (MyGenostics, Beijing, China) according to the manufacturer’s depth was 191.5× and included 98.2% of the targeted regions instructions. (Figure 1). These results suggested
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