IARS2

Inheritance Pattern: AR

Disease ID:MONDO:0014455

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between IARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2019. The IARS2 gene encodes mitochondrial isoleucyl-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 oxidative phosphorylation complex protein subunits. The IARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 25130867). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in two cases from two publications (PMIDs: 25130867, 30041933). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in a syndrome known by the acronym CAGSSS (cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia) which is a distinct clinical entity from the Leigh syndrome spectrum. This gene-disease association is also supported by known biochemical function and expression (PMIDs: 29980628, 25613900). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel November 20, 2019 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *IARS2* and *IARS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2024. The *IARS2* gene encodes mitochondrial isoleucyl-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 oxidative phosphorylation complex protein subunits. The *IARS2* gene was first reported in relation to autosomal recessive *IARS2*-related primary mitochondrial disease in 2014 (PMID: 25130867). *IARS2* has been associated with one disease entity to date; cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, or CAGSSS [OMIM# 616007]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *IARS2*-related primary mitochondrial disease. Of note, *IARS2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on November 20, 2019 (SOP v7), with a final classification of Limited. This current curation for the association with *IARS2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 17 unique variants (11 missense, three nonsense, two frameshift, and one deletion spanning exons 1 and 2) identified in 10 unrelated cases from eight publications (PMIDs: 25130867, 30419932, 28328135, 33327715, 35228874, 36704128, 39169373, 30041933). Disease onset is early in life. Clinical features in affected individuals include LSS, developmental delay and regression, seizures including infantile spasms, dystonia, peripheral neuropathy, cataracts, sensorineural hearing loss, short stature, growth hormone deficiency, adrenal insufficiency, hypoparathyroidism, skeletal dysplasia, sideroblastic anemia, exocrine pancreatic dysfunction, cardiomyopathy, Wolff-Parkinson-White arrhythmia, and elevated lactate. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration in non-patient cells (PMID: 39169373), an embryonic lethal knockout mouse model (PMID: 36305825), and a study performing shRNA knockdown in HEK293T cells with rescue (PMID: 39169373). In summary, there is definitive evidence to support the relationship between *IARS2* and autosomal recessive *IARS2*-related 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 December 16, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0014455

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014455

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014455

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0014455

Submitter: Labcorp Genetics (formerly Invitae)