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EARS2 (HGNC:29419) has been robustly implicated in leukoencephalopathy with thalamus and brainstem anomalies-high lactate syndrome (MONDO_0013971), a mitochondrial disorder marked by characteristic neuroimaging findings, feeding difficulties (PMID:25854774), hypotonia (PMID:25854774), and additional neurological features including seizures and global developmental delay (PMID:27117034). The phenotype spans from severe early-onset to milder presentations, reflecting the variable expressivity observed across reported cases.
Genetic evidence is strong and derives from multiple independent case reports. Several studies, including those published in JIMD reports (2015) (PMID:25854774), Brain & Development (2016) (PMID:27117034), Neuropediatrics (2016, 2017) (PMID:26619324; PMID:27875839), and Genes (2020) (PMID:32887222), describe affected probands harboring autosomal recessive mutations. For example, the truncating variant c.376C>T (p.Gln126Ter) exemplifies the deleterious changes observed, and segregation analyses in these families further support pathogenicity.
Multi‐patient studies have expanded the clinical spectrum and reinforced the genetic association by identifying both compound heterozygous and homozygous mutations in EARS2 across unrelated families. The diverse variant spectrum includes missense, nonsense, and frameshift changes that converge on a common defect in mitochondrial protein translation. Recurrent findings across studies, with citations such as (PMID:32887222), further validate the genetic contribution of EARS2 to the disease phenotype.
Functional studies have provided critical experimental evidence supporting the pathogenic role of EARS2 variants. In vitro assays using patient-derived fibroblasts have demonstrated significant mitochondrial dysfunction, as evidenced by decreases in oxygen consumption and reduced levels of EARS2 protein. Rescue experiments, where wild-type EARS2 restored normal mitochondrial function, corroborate the mechanistic link between the genetic defect and the metabolic phenotype (PMID:28748214; PMID:33855712).
Although one study noted that in vitro functional deficits may not always translate directly to an overt clinical phenotype (PMID:28748214), the preponderance of data across genetic and functional assessments firmly supports the disease association. Minor discordant observations do not detract from the overall evidence, as the bulk of independent reports and experimental assays show concordance with the clinical presentations of LTBL.
In summary, the collective genetic and experimental evidence assigns a strong gene-disease association between EARS2 and leukoencephalopathy with thalamus and brainstem anomalies-high lactate syndrome. This information is invaluable for diagnostic decision-making, guiding variant interpretation, and reinforcing the clinical utility of genetic testing in patients with suspected mitochondrial disorders.
Gene–Disease AssociationStrongMultiple independent case reports (e.g., 5 probands as indicated by PMID:25854774, PMID:27117034, PMID:26619324, PMID:27875839, and PMID:32887222) support autosomal recessive inheritance with compound heterozygous and homozygous mutations, along with robust segregation and clinical data. Genetic EvidenceStrongGenetic findings include a diverse variant spectrum—exemplified by the truncating variant c.376C>T (p.Gln126Ter)—across unrelated probands, confirming the pathogenic role of EARS2 in LTBL. Functional EvidenceModerateFunctional studies demonstrate significant mitochondrial dysfunction in patient-derived cells with EARS2 mutations, and rescue experiments restore function despite some conflicting in vitro observations. |