CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?

Abstract

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS.

Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression).

Results: We identified 3 new variants in cases, but only 1 was ALS-specific. Also, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p = 0.86, p = 0.86, and p = 0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness.

Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants. Ann Neurol 2018;83:110-116.

Figure 1. Non-synonymous CHCHD10 variants in neurodegenerative diseases

Overview of rare non-synonymous variants in ALS and other neurodegenerative diseases and their exonic location in CHCHD10. The top panel shows depth of coverage of CHCHD10 in the ExAC public database (orange) and Project Mine whole-genome sequencing data (blue-grey) (http://databrowser.projectmine.com). The grey panel shows all variants reported in pure ALS ± FTD; variants in green were present in multiple seemingly unrelated cases and absent in controls, orange variants were identified in both cases as well as controls and red variants were found in a single ALS case. The light grey panel shows variants reported in a more extensive phenotype that includes motor neuron disease. The bottom panel shows all variants and their location that were reported in other neurodegenerative diseases (MM = mitochondrial myopathy, PD = Parkinson’s disease, SMAJ = late onset spinal motor neuronopathy, CMT2 = Charcot-Marie Tooth Type 2).