EARS2

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between EARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The EARS2 gene encodes mitochondrial glutamyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of protein subunits of oxidative phosphorylation complexes I, III, IV, and V. The EARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22492562). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included twelve unique variants identified in eight cases from four publications (PMIDs: 22492562, 27206875, 27571996, 27117034). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and functional alterations in patient cells (PMIDs: 29980628, 27977873, 22492562). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013971

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *EARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 19, 2024. *EARS2* encodes mitochondrial glutamyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of protein subunits of oxidative phosphorylation complexes I, III, IV, and V. *EARS2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22492562). While various names have been given to the constellation of features seen in those with *EARS2*-related disorders (including leukoencephalopathy with thalamus and brainstem involvement and high lactate, LTBL), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the EARS2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *EARS2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on February 26, 2020 (SOP V7), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 17 variants (12 missense, one initiation codon, two nonsense, one frameshift, one splice) variants from 10 probands across six publications (PMIDs: 22492562, 27117034, 27206875, 27571996, 36349561, 32802952). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Affected individuals presented with a range of clinical features including LSS, developmental delay, developmental regression, seizures, ophthalmoplegia, hepatopathy, poor feeding, and lactic acidosis. Prenatal onset was reported in at least one family (PMID: 36349561). Decreased activities of mitochondrial respiratory chain enzyme complexes I, III, and IV were seen in muscle and skin fibroblasts. This gene-disease association is also supported by the known biochemical function of *EARS2* in mitochondrial translation, functional alteration in patient cells, and rescue in patient cells (PMIDs: 22492562, 33855712). In summary, there is definitive evidence to support the relationship between *EARS2* 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 September 19, 2024 (SOP Version 10).