blindness; heterogeneity; therapy; next generation sequencing (NGS); diagnostic testing; retina
Vincent A Ng J Gerth-Kahlert C Tavares E Maynes JT Wright T Tiwari A Tumber A Li S, Hanson JV Bahr A MacDonald H Bähr L Westall C Berger W Cremers FP den Hollander AI Héon E (2016), Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis., in Invest Ophthalmol Vis Sci
, 57(6), 2637-2646.
Tiwari A Lemke J Altmueller J Thiele H Glaus E Fleischhauer J Nürnberg P Neidhardt J, Berger W (2016), Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES): Benefits and Limitations., in PLoS One
, 11(7), e0158692.
Tiwari A Bahr A Bähr L Fleischhauer J Zinkernagel MS Winkler N Barthelmes D Berger L, Gerth-Kahlert C Neidhardt J Berger W (2016), Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies., in Sci Rep
, 29(6), 28755.
Haghighi Alireza, Tiwari Amit, Piri Nilofaar, Nuernberg Gudrun, Saleh-Gohari Nasrollah, Haghighi Amirreza, Neidhardt John, Nuernberg Peter, Berger Wolfgang (2014), Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous COL18A1 Mutation Causing Knobloch Syndrome, in PLOS ONE
, 9(11), 1-8.
Retinal degenerations and dysfunctions are characterized by a tremendous genetic heterogeneity and clinical variability of symptoms. More than 20 different clinical diagnoses involve mutations in more than 170 genes. Some of them are accompanied by extraocular clinical manifestations (syndromic forms), including for example deafness, mental retardation or renal abnormalities. During the last 3 years, therapeutic intervention has become a reality for these so far untreatable diseases, although it is not yet clinical routine. The eye is an ideal target for therapeutic applications because of its unique anatomical structure, easy accessibility and immune privilege. However, genetic heterogeneity and clinical variability require efficient and reliable diagnostic tests in order to apply specific treatment. So far, high throughput genetic testing is not available for patients with these diseases. We will make use of next generation sequencing and establish an efficient diagnostic strategy to screen for mutations in more than 170 known retinal disease genes. In addition, more than three thousands of candidate genes have been selected and will also be included in the screening. This strategy will lead to the identification of disease-causing mutations in known genes but also sequence variations in novel genes, which will unravel new biological processes underlying these diseases. Moreover, this approach will enable us to detect possible disease-modifying sequence variations.Mutations leading to aberrant splicing are among the most frequent causes of monogenetic disorders including retinal diseases. We have successfully developed a gene therapeutic approach to correct splice defects. Our future plans involve the systematic evaluation of this novel technique. As an experimental basis, we will establish a cell line collection of cultured fibroblasts and transformed lymphoblastoid cells from patients who underwent next generation sequencing.The projects´ objectives can be summarized as (i) generation and evaluation of a new diagnostic approach using next generation sequencing, (ii) identification and characterization of new mutations in known genes, (iii) identification of novel disease-associated genes and unravelling biological mechanisms leading to retinal diseases and (iv) development of therapeutic interventions for treatment of splicing defects.