Submission Details

CHCHD10 codes for the coiled-coil-helix-coiled-coil-helix domain containing 10 protein, a mitochondrial protein that is involved in oxidative phosphorylation and cristae morphology maintenance. CHCHD10 has been reported to cause ALS-FTD, mitochondrial myopathy, and late onset spinal muscular atrophy (Jokela type). Mitochondrial myopathy was determined to be an independent disease entity and was spilt from the CHCHD10 curation; however, evidence related to ALS, ALS/FTD, FTD, and late onset spinal muscular atrophy were considered. CHCHD10 was first reported to be responsible for autosomal dominant ALS-FTD in a large, five-generation family of French ancestry through exome sequencing and segregation analysis within the family. At least 17 variants in the CHCHD10 gene have since been reported to cause ALS-FTD in humans of diverse geoancestry across several publications (PMID: 24934289, 25726362, 25113787, 25261972, 25576308, 25155093, 25681414, 25833818, 26152333, 29789341, 26719383, 27056076). However, several reported variants have relatively high minor allele frequencies in population databases (>0.000005 in gnomAD) and were not scored as genetic-level evidence. Notably, the R15L variant in CHCHD10 was consistently reported to cause ALS-FTD across several populations and has functional evidence to support its disruption of mitochondrial function (PMID: 29121267). There is one variant in CHCHD10 that has been reported to cause late onset spinal muscular atrophy (Jokela type) in several families of Finnish ancestry (Gly66Val). This variant was not scored due to high frequency in population databases in the European Finnish population specifically (0.0001891 in gnomAD) (PMID: 21715705, 27810918).

Overall evidence supporting the CHCHD10 gene-disease relationship includes case-level data and experimental data. Postmortem analysis of a patient with CHCHD10 ALS (R15L) identified numerous aggregates of CHCHD10 within the anterior horns (PMID: 32042922). A knock-in mouse study (R15L) demonstrated that mutant mice develop progressive motor deficits, abnormal morphology and innervation of the neuromuscular junction, and accelerated mortality (PMID: 30877432). Protein interaction studies have demonstrated that CHCHD10 mutations induce cytoplasmic TDP-43 mis localization, potentiate TDP-43-induced apoptosis and synaptic impairment, and induce insoluble TDP-43 and (PMID: 28585542, 33772006).

In summary, there is moderate evidence to support a gene-disease relationship between CHCHD10 and frontotemporal dementia and/or amyotrophic lateral sclerosis 2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen ALS GCEP on the meeting date September 13, 2022 (SOP Version 9).