IARS1 – growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

Bi‐allelic variants in IARS1 cause an autosomal recessive GRIDHH phenotype characterized by growth delay, intellectual disability, hypotonia, and infantile hepatopathy. We report one additional unrelated proband harboring compound heterozygous missense variants c.701T>C (p.Leu234Pro) and c.1555C>T (p.Arg519Cys), presenting with severe growth retardation, muscular hypotonia, intellectual disability and recurrent liver failure leading to death at 19 months (PMID:35668413). No segregation data beyond the index case are available.

Functional assays support a loss‐of‐function mechanism: zebrafish embryo modeling recapitulated defects in growth, neurodevelopment, liver formation, and myogenesis concordant with the human phenotype (PMID:35668413); a hypomorphic IARSV79L mouse model exhibited mitochondrial hepatopathy with elevated hepatic triglycerides and serum ornithine carbamoyltransferase; and siRNA knockdown in HepG2 cells reduced mitochondrial membrane potential and increased reactive oxygen species (PMID:37108118).

Key take‐home: Bi‐allelic missense IARS1 variants underlie GRIDHH via loss of function, and genetic testing enables definitive diagnosis.

References

• BMC Pediatrics • 2022 • Compound heterozygous variations in IARS1 cause recurrent liver failure and growth retardation in a Chinese patient: a case report. PMID:35668413
• International Journal of Molecular Sciences • 2023 • Molecular and Pathological Analyses of IARS1-Deficient Mice: An IARS Disorder Model. PMID:37108118

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