Submission Details

The relationship between CHCHD10 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2023. CHCHD10 encodes a small protein called coiled-coil-helix-coiled-coil-helix domain containing 10 that localizes to the mitochondrial intermembrane space. While the exact mechanism of disease has not been fully elucidated, it appears that it is involved in mitochondrial genome stability and maintenance of cristae junctions. Defects of this protein are associated with mitochondrial fragmentation and/or trigger the mitochondrial integrated stress response.

CHCHD10 was first reported in relation to autosomal dominant primary mitochondrial disease in 2014 (PMID: 24934289), in two adults with late onset motor neuron disease characterized by dysphagia, dysarthria, areflexia, myopathy and cognitive impairment. While various names have been given to the constellation of features seen in those with CHCHD10-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the CHCHD10 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique missense variants identified in seven probands from six publications (PMIDs: 25428574, 25833818, 25113787, 35700042, 25193783, 24934289). Of note, toxic gain-of-function appears to be the disease mechanism for the p.Ser59Leu and p.Gly58Arg variants and loss-of-function appears to be the disease mechanism for other variants such as the p.Arg15Leu (PMID: 36158221). Affected individuals have a broad spectrum of features including mitochondrial myopathy with or without cardiomyopathy, motor neuron disease, Charcot Marie Tooth-like phenotypes, and spinal muscular atrophy. While the evidence for primary mitochondrial pathology is less clear in some of these cases, this Expert Panel agreed that these clinical phenotypes are within the spectrum of primary mitochondrial disease and opted to include them in this curation with conservative scoring. Familial segregation was also included in this curation (PMID: 25193783).

This gene-disease association is also supported by its known biochemical function and numerous knock-in mouse models of different variants (PMIDs: 30877432, 35700042). Of note, not all animal model CHCHD10 knockouts display a phenotype (PMID: 29112723).

In summary, there is definitive evidence to support the relationship between CHCHD10 and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 18, 2023 (SOP Version 9).