The relationship between ELAC2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. The ELAC2 gene encodes the elaC ribonuclease Z 2 that is involved in mitochondrial RNA expression and processing, and is essential for tRNA maturation.
The ELAC2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23849775). While various names have been given to the constellation of features seen in those with ELAC2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the ELAC2 phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 15 variants (one nonsense, 11 missense, 3 splice site) from 10 individuals from two publications (PMIDs: 23849775, 31045291). More cases are reported in the medical literature but not included in this curation as the maximum case level score was reached. Affected individuals are variably affected and clinical features include hypertrophic cardiomyopathy, intrauterine growth restriction, developmental delay, hypotonia, muscle weakness, exercise intolerance, microcephaly, feeding difficulty, sensorineural hearing loss, and lactic acidosis. Muscle biopsies show mitochondria with increased size and abnormal cristae, ragged red fibers, COX-negative fibers, and variable respiratory chain enzyme complex deficiencies. A heart transplant was successful in at least one individual (PMID: 31045291).
Loss of function is the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, and model systems in mice and Drosophila melanogaster (PMIDs: 21593607, 23849775, 21146608, 34338278, 30126926).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 21, 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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