Towards Comprehensive Registration of DNA Sequence Variants Associated with Inherited Retinal Diseases in Leiden Open Variation Databases

Abstract

Purpose: Inherited retinal diseases (RD) display an impressive degree of allelic and genetic heterogeneity as nearly 10,000 mutations in >190 genes have been identified. Mutations in these genes account for 30% to 90% of cases, depending on the type of disease. Comprehensive genotyping of persons with inherited RD improves genetic counseling and the accuracy of disease prognoses. Moreover, genotyping identifies persons who are eligible for novel therapies. We are entering an era of routine testing for RD-associated defects, both in academic and non-academic centers. The identified known and novel variants are not published or deposited in open access databases. Sharing sequence variants and their associated phenotypes are at the heart of DNA diagnostics and it therefore is of utmost importance to register this information in publicly available databases.

Methods: The structure and use of RD-mutation databases need to meet the following criteria: 1). Web-based open access; 2). Registration of all published sequence variants; 3). Easy upload of new variants; 4). Accurate assessment of mutation data; 5). Regular updating. We propose the implementation of Leiden Open Variation Databases (LOVDs) for all RD genes in the next five years. LOVDs were previously created for 10 Usher syndrome-associated genes. A team of BS students and staff members in Islamabad, will collect all published sequence variants for the remaining RD genes, scrutinize them for their proper annotations, and upload them in gene-specific LOVDs. World-wide curators will check the new entries.

Results: ‘Empty’ LOVDs were created for all RD associated genes, and all published variants were registered for AIPL1, LCA5, RDH5, SEMA4A, and TULP1. Other mutation repositories previously were created for CEP290, NDP, and Bardet-Biedl syndrome-associated genes. These will be taken up in LOVDs. In 2013, variants of another 25 RD-associated genes will be deposited in LOVDs and the existing LOVDs will be updated every year.

Conclusions: The long-term success of this endeavor relies on a robust organization of sequence variant updating, proper curation, database maintenance, and a sound financial basis. It will also be vital to introduce compulsory deposition of sequence variants prior to publication submissions, and the compliance of diagnostic facilities worldwide to deposit unpublished variants in LOVDs.

Keywords: 604 mutations • 696 retinal degenerations: hereditary • 539 genetics