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Expanding the Clinical, Allelic, and Locus Heterogeneity of Retinal Dystrophies

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Expanding the Clinical, Allelic, and Locus Heterogeneity of Retinal Dystrophies ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies Nisha Patel, PhD1, Mohammed A. Aldahmesh, PhD1, Hisham Alkuraya, MD2,3, Shamsa Anazi, MSc1, Hadeel Alsharif, BSc1, Arif O. Khan, MD1,4, Asma Sunker, BSc1, Saleh Al-mohsen, MD5, Emad B. Abboud, MD6, Sawsan R. Nowilaty, MD6, Mohammed Alowain, MD7, Hamad Al-Zaidan, MD7, Bandar Al-Saud, MD5, Ali Alasmari, MD8, Ghada M.H. Abdel-Salam, MD9, Mohamed Abouelhoda, PhD1,10, Firdous M. Abdulwahab, BSc1, Niema Ibrahim, BSc1, Ewa Naim, BPharm1,10, Banan Al-Younes, MSc1,10, Abeer E. AlMostafa, BSc1,10, Abdulelah AlIssa, BSc1,10, Mais Hashem, BSc1, Olga Buzovetsky, PhD11, Yong Xiong, PhD11, Dorota Monies, PhD1,10, Nada Altassan, PhD1,10, Ranad Shaheen, PhD1, Selwa A.F. Al-Hazzaa, MD12, and Fowzan S. Alkuraya, MD1,13 Purpose: Retinal dystrophies (RD) are heterogeneous hereditary the likely candidate as AGBL5 and CDH16, respectively. We also disorders of the retina that are usually progressive in nature. The aim performed exome sequencing on negative syndromic RD cases of this study was to clinically and molecularly characterize a large and identified a novel homozygous truncating mutation in GNS in cohort of RD patients. a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in Methods: We have developed a next-generation sequencing assay DNAJC17 in a family with an apparently novel syndrome of retinitis that allows known RD genes to be sequenced simultaneously. We also pigmentosa and hypogammaglobulinemia. performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. Conclusion: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as Results: Our panel identified the likely causal mutation in novel disease candidates. >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identi- Genet Med advance online publication 10 September 2015 fied two novel disease loci on Chr2:25,550,180-28,794,007 and ­Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed Key Words: ciliopathy; exome; gene panel INTRODUCTION of rods, resulting in the classical triad of reduced peripheral The human retina plays a critical role in vision by converting vision (tunnel vision), night blindness (nyctalopia), and char- light energy in the visible range to electrical signals through acteristic changes in peripheral retina that can be detected by phototransduction in photoreceptors. Photoreceptors exist in clinical examination.1 Cone dystrophies, however, can pres- two morphologically and functionally distinct forms—cones ent with reduced central vision, scotoma, photophobia, and and rods—which are respectively responsible for photopic macular lesions detectable by fundoscopy. For reasons that are (daylight-adapted) and scotopic (dark-adapted) vision. The not fully understood, death of one type of photoreceptor is term “retinal dystrophy” (RD) is used to describe a hetero- often accompanied by death of the other type such that it can geneous group of hereditary disorders in which the loss of be difficult to determine the subtype of RD based on clinical photoreceptor function results in progressive visual impair- retinal examination in advanced stages, which constitutes a ment. The clinical variability of RD is driven primarily by the phenotyping challenge. distribution of the defect. Retinitis pigmentosa, for instance, is The genetic heterogeneity of RD is remarkable, with 232 dis- the most common RD and is characterized by progressive loss ease genes listed in RetNet as of February 2015 that span the The first two authors contributed equally to this work. 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 2Department of Ophthalmology, College of Medicine, Al-Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia; 3Department of Ophthalmology, Specialized Medical Centre Hospital, Riyadh, Saudi Arabia; 4Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; 5Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 6Vitreo-retinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; 7Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 8Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia; 9Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt; 10Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; 11Department of Structural Biology, College of Medicine, Yale University, New Haven, Connecticut, USA; 12Department of Ophthalmology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 13Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. Correspondence: Fowzan S. Alkuraya ([email protected]) Submitted 18 May 2015; accepted 4 August 2015; advance online publication 10 September 2015. doi:10.1038/gim.2015.127 554 Volume 18 | Number 6 | June 2016 | GeneticS in medicine Expanding the heterogeneity of retinal dystrophies | PATEL et al ORIGINAL RESEARCH ARTICLE entire spectrum of Mendelian (autosomal recessive, autosomal Vision loss panel assay dominant, and X-linked) and non-Mendelian (mitochondrial This assay was part of a comprehensive “Mendeliome” assay and, very rarely, digenic). The study of RD genetics has greatly in which all established disease genes in OMIM as of August improved our understanding of the molecular biology of vision.2 2013 were divided into 13 clinically themed partially over- Genes that encode components of the connecting cilium (a mod- lapping gene panels, which is described in detail elsewhere.14 ified primary cilium that connects the outer and inner segments One of these panels is the “Vision Panel,” which included 322 of photoreceptors) are among the most commonly mutated genes known to cause Mendelian eye diseases, including RD. genes in RD, but genes encoding components of phototransduc- The panel was used to analyze the entire study cohort. Briefly, tions, lipid metabolism, ion channels, extracellular matrix, retina a next-generation multiplexing assay was developed whereby development, intermediary metabolism, cytoskeleton, and RNA the OMIM database was manually curated for genes with con- splicing are also known to be mutated in RD patients.3 Clinically, firmed causal links to diseases. The resulting list of ~3,000 the determination of the underlying mutation in RD is of imme- genes was included in 13 clinically themed panels, includ- diate translational benefit in terms of reproductive planning and, ing the Vision Panel used in this study. Genes were amplified more recently, choosing eligible patients for gene therapy for a using the AmpliSeq HiFi mix and proprietary primer design small but growing number of RD disease genes.4 (Thermo Fisher, Carlsbad, CA), followed by sequencing on the Despite its conspicuous basic and translational benefits, the Ion Proton platform following the manufacturer’s protocol. For study of RD genetics faces several important challenges. The the purpose of this article, we describe the results of the Vision marked locus and allelic heterogeneity of RD make it difficult to Panel only as they pertain to the RD cohort. The variant filter- identify the causal mutation in patients, which is further com- ing pipeline using the Saudi Human Genome is described else- pounded by the inadequate genotype/phenotype correlation.5 where.14 Briefly, only runs of high quality were aligned to the Some RD disease genes are known to underlie more than reference hg19 sequence and processed for variant calling using one clinically distinct subtype. In addition, the current list of the Torrent Suite Variant Caller program. In the subsequent RD disease genes is incomplete, so a significant proportion step, the variants were annotated using public-knowledge data- of patients will remain undiagnosed molecularly even if they bases available in the Annovar package and other commercial are screened for mutations in all these genes.6 Massively par- data sets such as the Human Gene Mutation Database, as well allel sequencing (also known as next-generation sequencing) as in-house databases comprising collections of disease-causing has ushered in a new era in molecular diagnostics by making variants. Variants that are less likely to play a functional role it feasible to sequence whole genomes, whole exomes, or large (intronic and synonymous), those with minor allele frequency panels of selected genes. This technology is particularly suited >1% and those with low base quality (using a Phred-like score for such a genetically and clinically heterogeneous condition produced by the Torrent Suite base caller) were excluded. The as RD, and this has been demonstrated by several studies.7–13 few remaining variants were then analyzed based on relevance In this study, we describe the application of a next-generation of gene to phenotype, zygosity (when indicated), and SIFT, sequencing-based gene panel strategy to study a very large PolyPhen, and combined annotation-dependent depletion cohort of RD patients in the diagnostic phase. In the
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