title: Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies.
abstract: Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population.
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.
authors.forename: Amit
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Bahr
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.
authors.forename: Luzy
authors.initials: L
authors.lastname: Bähr
authors.affiliation: Department of Ophthalmology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fleischhauer
authors.affiliation: Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Switzerland.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Zinkernagel
authors.affiliation: Department of Ophthalmology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
authors.forename: Niklas
authors.initials: N
authors.lastname: Winkler
authors.affiliation: Department of Ophthalmology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Barthelmes
authors.affiliation: Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Switzerland.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Berger
authors.affiliation: Department of Ophthalmology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Gerth-Kahlert
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.|Neuroscience Center Zurich (ZNZ), University and ETH Zürich, Zürich, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D011991:Receptors, Virus / Q000235:genetics*; D058499:Retinal Dystrophies / Q000453:epidemiology / Q000235:genetics*; D013557:Switzerland / Q000453:epidemiology; D000073359:Exome Sequencing
chemical_list: D005136:Eye Proteins; C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; C550125:PCARE protein, human; D011991:Receptors, Virus