Missense variants in the X‐linked gene PRPS1 cause retinal degeneration in females |
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Authors: | Alessia Fiorentino Kaoru Fujinami Gavin Arno Anthony G. Robson Nikolas Pontikos Monica Arasanz Armengol Vincent Plagnol Takaaki Hayashi Takeshi Iwata Matthew Parker Tom Fowler Augusto Rendon Jessica C. Gardner Robert H. Henderson Michael E. Cheetham Andrew R. Webster Michel Michaelides Alison J. Hardcastle |
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Affiliation: | 1. UCL Institute of Ophthalmology, London, United Kingdom;2. Moorfields Eye Hospital, London, United Kingdom;3. National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan;4. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan;5. UCL Genetics Institute, London, United Kingdom;6. Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan;7. Genomics England, Queen Mary University of London, London, United Kingdom;8. Sheffield Diagnostic Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom;9. Department of Haematology, University of Cambridge, Cambridge, United Kingdom;10. Great Ormond Street Hospital for Children, Great Ormond Street, London, United Kingdom |
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Abstract: | Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X‐linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot–Marie–Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X‐linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue‐specific skewed X‐inactivation or variable levels of pyrophosphate synthetase‐1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next‐generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation. |
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Keywords: | next‐generation sequencing PRPS1 PRS‐I retinal dystrophy |
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