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

• Published in: Annals of neurology Vol. 84; no. 1; pp. 110 - 116
• Main Authors: Tazelaar, Gijs H.P., van Rheenen, Wouter, Pulit, Sara L., van der Spek, Rick A.A., Dekker, Annelot M., Moisse, Matthieu, McLaughlin, Russell L., Sproviero, William, Kenna, Kevin P., Kooyman, Maarten, van Doormaal, Perry T.C., van Eijk, Kristel E., Middelkoop, Bas M., Schellevis, Raymond D., Brands, William J., Al‐Chalabi, Ammar, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Newhouse, Stephen E., van Es, Michael A., Basak, A. Nazli, Akçimen, Fulya, Kocoglu, Cemile, Tunca, Ceren, Povedano, Monica, Mora, Jesus S., Glass, Jonathan D., Van Damme, Philip, Robberecht, Wim, HardimanMD, Orla, Landers, John E., van den Berg, Leonard H., Veldink, Jan H.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2018
• Subjects: Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Deafness; DNA Mutational Analysis; Female; Genetic diversity; Genetic variance; Genomes; Humans; International Cooperation; Logistic Models; Male; Middle Aged; Mitochondria; Mitochondrial Proteins - genetics; Mutation; Mutation - genetics; Myopathy; Neural coding; Pathogenicity; Pathogens; Patients; Phenotypes; Regression analysis; Severity of Illness Index
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.25273

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