Reply: SCA23 and prodynorphin: is it time for gene retraction?

Sir,With the introduction of next generation sequencing into research and the clinic, geneticists now face the problem of variant interpretation in single cases, which is a challenging task due to the lack of data from additional affected family members. For the majority of the variants in our genome we do not know whether they are damaging and pathogenic or just harmless rare polymorphisms. We therefore must rely heavily on in silico prediction programs and the information found in large genetic databases such as ExAC [Exome Aggregation Consortium (ExAC), Cambridge, MA] (http://exac.broadinstitute.org) to predict the pathogenicity of variants. The letter from Pedroso et al. (2016) addresses this problem.Pedroso et al. (2016) state that many of the reported SCA23 mutations in PDYN are present in ExAC and suggest that this brings into question the validity of PDYN as the disease-causing gene for SCA23. They point out that the SCA23 mutations were detected in 37 of 60 700 individuals in ExAC, a database that was founded in 2014, 4 years after our original SCA23 report was published, when none of these PDYN variations had been detected in controls or any genetic database, supporting our conclusion that PDYN is the SCA23 disease gene. ExAC combines multi-ethnic sequencing data from several sources, as it includes sequencing studies on heart disease, type 2 diabetes, schizophrenia, bipolar disorder, and Tourette’s syndrome, …