Recurrent Acute Liver Failure and Neutropenia сaused by a novel homozygous RINT1 variant: evidence for a population-specific disorder

Abstract Background Recurrent acute liver failure in pediatric patients is a severe and life-threatening condition with heterogeneous genetic, immunologic, and environmental causes. Early diagnosis is critical to guide management and improve outcomes. The role of RINT1 variants in liver pathology has been underexplored, with limited data linking these mutations to hepatocellular dysfunction. Results We report an 8-year-old female proband from Chuvashia presenting with recurrent acute liver failure and neutropenia. Genetic analysis identified a homozygous RINT1 variant (NM_021930.6:c.1435G>C, p.Ala479Pro), with unaffected parents as heterozygous carriers. The proband experienced multiple episodes of fever- and infection-triggered liver failure, characterized by elevated alanine aminotransferase and aspartate aminotransferase levels, coagulopathy, hepatomegaly, and progressive liver fibrosis. Structural modeling using Alphafold revealed that the p.Ala479Pro variant is located within a conserved alpha-helical region of the RINT1/TIP20 domain, critical for protein stability and function. Population-specific analysis suggested the variant's origin in the Chuvash ethnic group, supporting its potential significance for genetic counseling. Additionally, we noted a novel clinical phenotype of RINT1-related disorders, including neutropenia, and described affected siblings with similar manifestations, further supporting an autosomal recessive inheritance pattern. Conclusions This case expands the clinical spectrum of RINT1-related disorders by associating RINT1 variants with recurrent liver failure and neutropenia. Early genetic diagnosis through whole-exome sequencing and vigilant monitoring are essential to optimize patient outcomes. The findings also emphasize the importance of population-specific analyses in identifying pathogenic variants and guiding genetic counseling. Structural insights from bioinformatics modeling further highlight the functional consequences of the p.Ala479Pro mutation, offering avenues for future research into targeted therapeutic strategies.