title: Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy.
abstract: Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction (qPCR) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2-negative patients with indistinguishable phenotypes from CYP4V2-positive patients might suggest the presence of mutations outside the coding regions of CYP4V2, or locus heterogeneity, which is unreported so far.
authors: Department of Human Genetics, Radboud University Medical Centre Nijmegen, The Netherlands ; Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre Nijmegen, The Netherlands ; Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine, Diponegoro University Semarang, Indonesia.
authors: Galuh D N
authors: GD
authors: Astuti
authors: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Centre Montreal, Quebec, Canada.
authors: Vincent
authors: V
authors: Sun
authors: Center for Medical Genetics, Ghent University Hospital Ghent, Belgium.
authors: Miriam
authors: M
authors: Bauwens
authors: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen Tübingen, Germany.
authors: Ditta
authors: D
authors: Zobor
authors: Center for Medical Genetics, Ghent University Hospital Ghent, Belgium ; Department of Ophthalmology, Ghent University Hospital Ghent, Belgium.
authors: Bart P
authors: BP
authors: Leroy
authors: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Centre Montreal, Quebec, Canada ; Moorfields Eye Hospital London, United Kingdom.
authors: Amer
authors: A
authors: Omar
authors: Department of Ophthalmology, University of Essen Essen, Germany.
authors: Bernhard
authors: B
authors: Jurklies
authors: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Centre Montreal, Quebec, Canada.
authors: Irma
authors: I
authors: Lopez
authors: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Centre Montreal, Quebec, Canada.
authors: Huanan
authors: H
authors: Ren
authors: Department of Human Genetics, Radboud University Medical Centre Nijmegen, The Netherlands.
authors: Volkan
authors: V
authors: Yazar
authors: Institute of Neurosciences of Montpellier, Hôpital Saint Eloi Montpellier, France.
authors: Christian
authors: C
authors: Hamel
authors: Rare Retinal Disease Center, AugenZentrum Siegburg, MVZ ADTC Siegburg GmbH Siegburg, Germany.
authors: Ulrich
authors: U
authors: Kellner
authors: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen Tübingen, Germany.
authors: Bernd
authors: B
authors: Wissinger
authors: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen Tübingen, Germany.
authors: Susanne
authors: S
authors: Kohl
authors: Center for Medical Genetics, Ghent University Hospital Ghent, Belgium.
authors: Elfride
authors: E
authors: De Baere
authors: Department of Human Genetics, Radboud University Medical Centre Nijmegen, The Netherlands ; Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre Nijmegen, The Netherlands.
authors: Rob W J
authors: RW
authors: Collin
authors: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Centre Montreal, Quebec, Canada.
authors: Robert K
authors: RK
authors: Koenekoop
keywords: Bietti; CYP4V2; crystalline dystrophy; retinal dystrophy
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