Reply: Evaluation of exome sequencing variation in undiagnosed ataxias

Sir,Erin Sandford and colleagues raise three main concerns that they believe undermine the likely causal nature of some of the genetic variants we detected by exome sequencing undiagnosed patients with ataxia (Pyle et al. , 2015): 1. Some of our proposed pathogenic variants have a minor allele frequency (MAF) of >0.01 in the population. Although useful as an initial guide, the 1% MAF is an arbitrary cut-off designed to rapidly filter-out common polymorphic genetic variants from a large exome data set. However, this must be done with care for several reasons. First, allele frequencies vary from database to database, and throughout the world. To choose their example, c.709C>T p.Pro237Ser in Patients P15 and P16 has a MAF = 0.0153 in the US-based ESP6500 (their Table 1), which contrasts with our local population (MAF = 0.0052), and the UK-based 1000 Genomes project (MAF = 0.0064). To our mind it would be ridiculous to reject this variant as non-pathogenic because one database documents a MAF > 0.01. Surely the important point here is …