The relationship between LYRM7 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The LYRM7 gene encodes LYR motif containing 7, which is a chaperone protein involved in the assembly of mitochondrial complex III. Defects of this protein lead to complex III deficiency.
The *LYRM7 *gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 24014394). While various names have been given to the constellation of features seen in those with LYRM7-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the LYRM7 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 six unique variants (one missense, one in-frame duplication, one splice region, one canonical splice site, one frameshift, and one stop-gained variant, each identified in a homozygous state) identified in seven unrelated individuals from two publications (PMIDs: 24014394, 26912632). More evidence is available in the literature (e.g., PMIDs: 28694194, 33189022, 33662890), but the maximum score for genetic evidence (12 pts.) has been reached. Features in affected individuals included leukoencephalopathy with cavitations in white matter, as well as neuroregression with illness and episodes of subacute encephalopathy. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in non-patient cells showing impaired mitochondrial function due to gene knockdown, and rescue of the mitochondrial dysfunction in a null yeast model following expression of the wildtype protein (PMIDs: 28844695, 23168492, 25914718).
In summary, there is definitive evidence to support the relationship between LYRM7 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 4, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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