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Whole-exome sequencing in the investigation of retinal dystrophy
Poster Abstracts
Whole-exome sequencing in the investigation of retinal dystrophy Sarah Hull, Gavin Arno, Nicholas Owen, Vincent Plagnol, Anthony Robson, Michel Michaelides, Graham Holder, Andrew Webster, Anthony Moore
Abstract Published Online February 25, 2016 Poster 29 University College London, London, UK (S Hull FRCOphth, G Arno PhD, N Owen DPhil, V Plagnol PhD, A Robson PhD, Prof M Michaelides FRCOphth, Prof G Holder PhD, Prof A Webster FRCOphth, Prof A Moore FRCOphth); Moorfields Eye Hospital, London, UK (S Hull, G Arno, A Robson, M Michaelides, G Holder, A Webster, A Moore); and University of California, San Francisco, CA, USA (A Moore) Correspondence to: Miss Sarah Hull, Department of Genetics, Moorfields Eye Hospital, London EC1V 2PD, UK [email protected]
Background Juvenile onset retinal dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset retinal dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations. Methods Patients were ascertained from the inherited retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee. Findings Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140-related retinal dystrophy in two families with no skeletal or renal manifestations of IFT140-related Mainzer-Saldino syndrome, COL18A1-related retinal dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome. Interpretation Early molecular diagnosis in early onset retinal dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed. Funding National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM). Contributors SH, GA, AW, and AM designed the project. SH, GA, and NO acquired the data. All authors reviewed the work, analysed and interpreted the data, and approved the final version of the abstract. Declaration of interests We declare no competing interests.
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Whole-exome sequencing in the investigation of retinal dystrophy Sarah Hull, Gavin Arno, Nicholas Owen, Vincent Plagnol, Anthony Robson, Michel Michaelides, Graham Holder, Andrew Webster, Anthony Moore
Abstract Published Online February 25, 2016 Poster 29 University College London, London, UK (S Hull FRCOphth, G Arno PhD, N Owen DPhil, V Plagnol PhD, A Robson PhD, Prof M Michaelides FRCOphth, Prof G Holder PhD, Prof A Webster FRCOphth, Prof A Moore FRCOphth); Moorfields Eye Hospital, London, UK (S Hull, G Arno, A Robson, M Michaelides, G Holder, A Webster, A Moore); and University of California, San Francisco, CA, USA (A Moore) Correspondence to: Miss Sarah Hull, Department of Genetics, Moorfields Eye Hospital, London EC1V 2PD, UK [email protected]
Background Juvenile onset retinal dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset retinal dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations. Methods Patients were ascertained from the inherited retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee. Findings Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140-related retinal dystrophy in two families with no skeletal or renal manifestations of IFT140-related Mainzer-Saldino syndrome, COL18A1-related retinal dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome. Interpretation Early molecular diagnosis in early onset retinal dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed. Funding National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM). Contributors SH, GA, AW, and AM designed the project. SH, GA, and NO acquired the data. All authors reviewed the work, analysed and interpreted the data, and approved the final version of the abstract. Declaration of interests We declare no competing interests.
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