Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants
Autor: | Pavel Diblik, Bohdan Kousal, Michaela Hejtmankova, Lubica Dudakova, Renata Gaillyova, Michel Michaelides, Petra Liskova |
---|---|
Rok vydání: | 2016 |
Předmět: |
Adult
Male 0301 basic medicine Proband Pathology medicine.medical_specialty Retinal Disorder Adolescent Genotype DNA Mutational Analysis Nerve Tissue Proteins Biology Compound heterozygosity Retina Young Adult 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound symbols.namesake 0302 clinical medicine Retinal Dystrophies Electroretinography medicine Humans Child Eye Proteins Genotyping Exome sequencing Sanger sequencing Genetics Homozygote Membrane Proteins Eye Diseases Hereditary Retinal Sensory Systems Pedigree Ophthalmology Phenotype 030104 developmental biology chemistry Mutation 030221 ophthalmology & optometry symbols Female |
Zdroj: | Graefe's Archive for Clinical and Experimental Ophthalmology. 254:1833-1839 |
ISSN: | 1435-702X 0721-832X |
Popis: | 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. 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. 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. 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. |
Databáze: | OpenAIRE |
Externí odkaz: |