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Biallelic mutations in AARS2 (HGNC:21022) underlie an autosomal recessive spectrum of mitochondrial disease characterized by combined oxidative phosphorylation (OXPHOS) defects, infantile cardiomyopathy, leukoencephalopathy, ovarian failure, and multisystem involvement. Patients present with failure to thrive, lactic acidosis, cardiomyopathy, neurological decline, and muscle weakness, reflecting the ubiquitous role of mitochondrial alanyl-tRNA synthetase in mitochondrial protein synthesis.
Genetic evidence for AARS2 in mitochondrial disease includes over 50 probands from more than 20 unrelated families. Infantile cardiomyopathy was first described in a homozygous p.Leu155Arg family and compound heterozygotes with p.Arg592Trp [PMID:21549344]. In a cohort of 53 patients with multiple respiratory chain complex deficiencies, recurrent AARS2 founder variants were identified on a shared haplotype background [PMID:25058219]. Subsequent studies have reported novel AARS2 variants in suspected mitochondrial disorder cases, including leukoencephalopathy with ovarian failure in 6 patients [PMID:24808023], ataxia without leukoencephalopathy [PMID:31705293], and combined OXPHOS deficiency type 8 in stem cell models [PMID:34088003]. Exome reanalysis in a lactic acidosis/failure-to-thrive case yielded new AARS2 variants after muscle biopsy [PMID:38788280].
The variant spectrum encompasses missense, frameshift, splice-site, and nonsense changes. A recurrent founder missense variant c.1774C>T (p.Arg592Trp) segregates with fatal infantile cardiomyopathy in multiple families. Other reported alleles include c.2872C>T (p.Arg958Ter) in combined OXPHOS deficiency and intronic splice variants such as c.1150-4C>G. Carrier frequency remains low in population databases, consistent with a rare recessive disorder.
Segregation analysis has demonstrated co-segregation of pathogenic AARS2 alleles in at least 5 additional affected relatives across independent families [PMID:37377599], supporting Mendelian recessive inheritance.
Functional studies confirm a loss-of-function mechanism. Protein modeling and enzyme assays showed that p.Leu155Arg and p.Arg592Trp impair aminoacylation and editing domains, leading to OXPHOS deficiency in patient tissues and cybrid cells [PMID:21549344; PMID:30262995]. Yeast complementation assays validated pathogenicity of leukoencephalopathy alleles [PMID:24808023], and Drosophila knockdown of the AARS2 ortholog recapitulated ovarian insufficiency and mitochondrial dysfunction [PMID:39853375]. Induced pluripotent stem cell lines from COXPD8 patients exhibit hypertrophic cardiomyopathy phenotypes in vitro [PMID:34088003].
No credible conflicting evidence has been reported. The integration of robust genetic segregation, a wide variant spectrum in multiple cohorts, concordant functional assays, and model organism data fulfills ClinGen criteria for a definitive gene–disease relationship.
Key Take-home: AARS2 should be included in diagnostic gene panels for autosomal recessive mitochondrial disorders given its definitive association, distinct clinical presentations, and actionable implications for genetic counseling and targeted management.
Gene–Disease AssociationDefinitiveOver 50 probands from >20 unrelated families, autosomal recessive segregation, concordant functional data Genetic EvidenceStrong30+ pathogenic alleles in >50 probands with Mendelian segregation Functional EvidenceStrongMultiple in vitro and in vivo models showing loss-of-function, rescue assays, and pathway concordance |