Retinitis pigmentosa: More genes, more variants, more work


Neveling et al. (Hum Mutat 33:963–972, 2012) studied patients with retinitis pigmentosa (RP), a disease hampered by extreme genetic and clinical heterogeneity; 52 causative genes have been described thus far. The authors designed a targeted approach to simultaneously analyze 111 candidate genes and developed and validated a data analysis pipeline to prioritize variants identified and to predict their functional consequences (“pathogenicity”). One hundred RP patients were studied, yielding 0-9 variants per patient prioritized for further analysis. For 36 RP patients (27 recessive, 6 dominant, 3 X-linked), a definitive diagnosis could be made. In 3/28 isolated cases, de novo causative variants were identified, which has major implications for RP counseling.

The paper by Neveling et al. demonstrates the next step in the diagnostics of genetic disease. A few years ago, we could barely afford to analyze candidate disease genes one at a time. Nowadays, due to the stunning developments in sequencing technology, reduced sequencing cost allows the analysis of large gene sets. In the near future, we will be able to do full exome/genome analysis. However, with this will come a flood of variation data that must be made available.

Human Mutation requires authors to submit all gene variants to locus-specific databases (LSDBs). This decision originally created a significant workload for the authors, which was solved with the help of the Leiden Open Variation Database (LOVD) team of database engineers and curators. If an LSDB is not available for a specific gene, one can be created rapidly. If several databases exist for one gene, the LOVD system can send data to all of them. The existing LSDBs for RP are spread over several sites, using different formats for data submission (some E-mail based only). While work needs to be done to reduce the amount of effort involved in data submission for large multigenic studies like the this one, the benefit to research communities of collecting and providing gene variation data will be profound.