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Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

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Abstract

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

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Acknowledgments

We gratefully acknowledge all participating patients and their family members. NGS was conducted at the Functional Genomic Core (FGC) facility at Baylor College of Medicine supported by NIH shared instrument grant 1S10RR026550 to R.C. This work was supported by grants from the Retinal Research Foundation, Foundation Fighting Blindness and the National Eye Institute (R01EY022356) to R.C. K.Z. acknowledges supports from the National Eye Institute (P30EY022589, R01EY021374, and RO1EY018660), the King Abdulaziz City for Science and Technology through the UC San Diego Center of Excellence in Nanomedicine, Veterans Affairs Merit Award, Research to Prevent Blindness, and Burroughs Wellcome Fund Clinical Scientist Award in Translational Medicine. R.K.K. acknowledges supports from the Foundation Fighting Blindness Canada, the CIHR, Reseau Vision, FRSQ, NIH, and McGill University Health Centre. S.P.D acknowledges grants from the Foundation Fighting Blindness and National Institutes of Health Grant EY007142. F.W. is supported by predoctoral fellowship: The Burroughs Wellcome Fund, The Houston Laboratory and Population Sciences Training Program in Gene Environment Interaction. J.Z. is supported by NIH training grant T32 EY007102 and NLM training fellowship T15 LM007093. X.W. is supported by predoctoral fellowship: The Burroughs Wellcome Fund, The Houston Laboratory and Population Sciences Training Program in Gene Environment Interaction. We thank Ms. Kristin Rauscher for assistance in sample preparation. We thank Mr. Naimesh Solanki for assistance in sequencing library preparation. We sincerely thank Ms. Renee Pigeon and Ms. Shirley Briand for their help in coordinating the patients.

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Correspondence to Robert K. Koenekoop, Kang Zhang or Rui Chen.

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Wang, F., Wang, H., Tuan, HF. et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet 133, 331–345 (2014). https://doi.org/10.1007/s00439-013-1381-5

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