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The association between LARS1 and infantile liver failure syndrome type 1 (ILFS1) is supported by multiple independent clinical observations. Several studies have described affected individuals presenting with severe neonatal liver dysfunction, intrauterine growth retardation, encephalopathy, failure to thrive, microcytic anemia, and anasarca (PMID:30349989, PMID:33300650). Reports include case series and multi‐patient studies documenting both isolated and compound heterozygous variants in LARS1. This cumulative evidence spans several years and ethnic backgrounds, reinforcing the critical link between LARS1 dysfunction and ILFS1. The detailed clinical and molecular characterization across these reports enhances confidence in the gene–disease relationship. Genetic testing, therefore, plays a pivotal role in arriving at a precise diagnosis in affected neonates.
Overall, the clinical validity of the association is rated as Definitive. At least 36 patients have been reported across more than 15 families (PMID:25917789, PMID:32699352), with robust segregation demonstrated in affected relatives and replication of findings in independent cohorts. The consistent observation of pathogenic variants in multiple studies and the integration of genetic testing into clinical practice underscore the strength of this association. Genetic data combined with detailed patient phenotyping have reached the ClinGen scoring maximum. These findings offer significant diagnostic reassurance and form a foundation for potential therapeutic exploration.
Genetic evidence is robust in this condition. The disorder follows an autosomal recessive pattern with confirmed compound heterozygosity in several affected individuals. Reported variants include missense changes, frameshift mutations, and recurrent truncating alleles. Notably, the variant c.1292T>A (p.Val431Asp) has been identified in at least one proband (PMID:30349989). Familial segregation studies have demonstrated that additional affected relatives harbor the same pathogenic variants, reinforcing the causative link. This collective genetic evidence validates the use of comprehensive sequencing in suspected cases of ILFS1.
Experimental data further support the pathogenicity of LARS1 mutations. Functional assays in zebrafish models reveal that loss of LARS1 function yields liver failure phenotypes that closely mirror the human disorder, including impaired liver synthetic function and enhanced autophagy (PMID:30262142). In these models, inhibition of mTORC1 signaling using Rapamycin partially rescues the hepatic defects, clarifying the downstream molecular mechanism. These findings are consistent with in vitro studies that demonstrate a loss of aminoacylation activity upon mutation. Collectively, the experimental evidence provides a mechanistic insight—namely, a loss-of-function effect leading to disrupted protein synthesis and metabolic regulation—that supports clinical observations.
While some studies have reported additional phenotypes such as neurological manifestations and features overlapping with other metabolic disorders, these have not diluted the fundamental association between LARS1 and ILFS1. The bulk of the clinical data remains focused on the severe hepatic and extrahepatic manifestations characteristic of ILFS1. Minor discrepancies in phenotypic presentation are likely attributable to allelic heterogeneity and environmental modifiers. Importantly, conflicting reports have not provided sufficient evidence to refute or substantially weaken the clinical association. Instead, they highlight the complexity of the disorder and underscore the need for continued phenotypic refinement in future studies.
In conclusion, the integration of comprehensive genetic analyses with functional studies provides definitive evidence linking LARS1 mutations to infantile liver failure syndrome type 1. The clear demonstration of autosomal recessive inheritance, consistent segregation across families, and corroborative experimental data firmly establish the clinical utility of genetic testing for LARS1 in suspected ILFS1 cases. Key take‑home: Timely and accurate molecular diagnosis of ILFS1 is essential for guiding clinical management and has the potential to improve patient outcomes.
Gene–Disease AssociationDefinitiveMultiple independent studies reporting over 36 patients from more than 15 families with ILFS1 (PMID:25917789, PMID:32699352); extensive segregation and robust functional zebrafish model data (PMID:30262142) support a definitive association. Genetic EvidenceStrongCase reports document a spectrum of variants including missense and truncating mutations, such as c.1292T>A (p.Val431Asp) (PMID:30349989), with clear autosomal recessive inheritance and segregation across families. Functional EvidenceModerateFunctional studies using zebrafish models demonstrate liver dysfunction that mimics the human phenotype and partial rescue with mTORC1 inhibition, supporting the loss-of-function mechanism (PMID:30262142). |