Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?

Sir, A recent study by Bannwarth et al. (2014) in Brain identified a novel mutation (c.176C4 T; p.Ser59Leu) in the CHCHD10 gene that segregates in a family presenting with ataxia, myopathy, hearing loss as well as motor neuron disease and frontotemporal dementia (FTD). Furthermore they identified a second family with ALS/FTD harbouring the identical mutation making this a gene of interest in the pathogenesis of ALS/FTD. For this reason we read with great interest the letter by Müller et al. (2014) that describes the identification of two novel variants in CHCHD10 in three pedigrees with familial amyotrophic lateral sclerosis (ALS). The authors state that their findings provide strong support for CHCHD10 being a novel ALS gene. Although their findings are highly interesting and their conclusion is appealing, we feel obliged to make several remarks concerning the genetic evidence provided to support this statement. The definition of genetic evidence, driven by the problem of non-replicating findings, is a matter of concern over the past years and has led to multiple consensus definitions for different study designs (reviewed by Pulit et al., 2014). A landmark paper published nearly 20 years ago defined segregation of the gene with the studied phenotype within a pedigree resulting in a LOD score53 as robust genetic evidence (Lander and Kruglyak, 1995). For genome-wide association studies the problem of multiple testing was overcome by adopting a significance threshold of P55 10 8 on a genome-wide level and P5 5 10 7 on an exome-wide level (Dudbridge et al., 2008; Pe’er et al., 2008; Do et al., 2012). Although these measures might seem conservative and are hard to meet in smaller studies, relaxing these thresholds in the past has led to an unfortunately high number of false positive associations: of 166 associations with more than two follow-up studies, only six (3.6%) replicated (Hirschhorn et al., 2002). In the study by Müller et al. (2014) whole exome sequencing data for 125 index patients from different ALS pedigrees was obtained, which is a common start-off point in a hypothesisgenerating study to find new ALS genes (Müller et al., 2014). The results presented, however, include the results for CHCHD10 only. The question is to what extent this study truly represents a replication approach since the authors investigate all variants in CHCHD10 among familial ALS cases and the report by Bannwarth et al. (2014) identified one specific CHCHD10 mutation in a very distinct sub-phenotype of ALS/FTD. Furthermore, since it is unlikely that this data set will be used to test this hypothesis exclusively, their results should be seen in the context of a large exome-wide hypothesis-generating search that goes along with the burden of multiple testing requiring stringent control of false positive findings. After identifying two novel mutations (p.Arg15Leu and p.Gly66Val) in three different pedigrees the authors state that there is an autosomal dominant mode of inheritance with incomplete penetrance. Unfortunately, the authors do not provide LOD score calculations, taking potential non-penetrance into account, which could support segregation within these pedigrees. Indeed, screening in pedigree B identified the mutation in four out of six unaffected family members and pedigree A includes three obligate carriers that are apparently unaffected. Although it is not impossible for the p.Arg15Leu mutation to be the causal variant in these pedigrees, one could argue that the high number of unaffected carriers pleads against this and raises the question doi:10.1093/brain/awu299 Brain 2014: 137; 1–2 | e313