Bohdan Kousal1,2, Lubica Dudakova2, Renata Gaillyova3, Michaela Hejtmankova4, Pavel Diblik1, Michel Michaelides5,6, Petra Liskova7,8. 1. Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. 2. Institute of Inherited Metabolic Disorders,General Teaching Hospital and First Faculty of Medicine, Charles University, Ke Karlovu 2, Praha 2, 128 08, Prague, Czech Republic. 3. Department of Genetics, Faculty Hospital, Brno, Czech Republic. 4. GENNET, Prague, Czech Republic. 5. Moorfields Eye Hospital NHS Foundation Trust, London, UK. 6. UCL Institute of Ophthalmology, London, UK. 7. Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. petra.liskova@lf1.cuni.cz. 8. Institute of Inherited Metabolic Disorders,General Teaching Hospital and First Faculty of Medicine, Charles University, Ke Karlovu 2, Praha 2, 128 08, Prague, Czech Republic. petra.liskova@lf1.cuni.cz.
Abstract
PURPOSE: The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype. METHODS: DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings. RESULTS: All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer. CONCLUSIONS: The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.
PURPOSE: The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype. METHODS: DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings. RESULTS: All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer. CONCLUSIONS: The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.
Authors: Johan T den Dunnen; Raymond Dalgleish; Donna R Maglott; Reece K Hart; Marc S Greenblatt; Jean McGowan-Jordan; Anne-Francoise Roux; Timothy Smith; Stylianos E Antonarakis; Peter E M Taschner Journal: Hum Mutat Date: 2016-03-25 Impact factor: 4.878
Authors: Samuel G Jacobson; Artur V Cideciyan; Tomas S Aleman; Michael J Pianta; Alexander Sumaroka; Sharon B Schwartz; Elaine E Smilko; Ann H Milam; Val C Sheffield; Edwin M Stone Journal: Hum Mol Genet Date: 2003-05-01 Impact factor: 6.150
Authors: Ivan A Adzhubei; Steffen Schmidt; Leonid Peshkin; Vasily E Ramensky; Anna Gerasimova; Peer Bork; Alexey S Kondrashov; Shamil R Sunyaev Journal: Nat Methods Date: 2010-04 Impact factor: 28.547
Authors: Pablo Altschwager; Lucia Ambrosio; Emily A Swanson; Anne Moskowitz; Anne B Fulton Journal: Semin Pediatr Neurol Date: 2017-05-23 Impact factor: 1.636