Hum Genomics. 2025 Oct 7;19(1):116. doi: 10.1186/s40246-025-00827-5.
ABSTRACT
BACKGROUND: Recurrent acute liver failure (RALF) is a rare and life-threatening disorder often triggered by infections or febrile episodes. Variants in genes regulating vesicular transport, including RINT1, NBAS have been implicated in RALF and are classified as infantile liver failure syndromes type 2 and 3 (ILFS2 and ILFS3), often associated with multisystemic manifestations.
METHODS: We conducted comprehensive clinical, laboratory and genetic evaluations of a proband presenting with RALF and neutropenia. Whole-exome sequencing (WES), whole-genome sequencing (WGS), Sanger analysis, autozygosity mapping and 3D protein structural modeling were conducted to identify and characterize the pathogenic variant.
RESULTS: A novel homozygous variant in the RINT1 gene (NM_021930.6:c.1435G > C, p.Ala479Pro) was identified in a proband from Chuvashia presenting with RALF and neutropenia, with both parents confirmed as heterozygous carriers. Structural modeling suggested a destabilizing effect on the RINT1/TIP20 domain. Two siblings with identical symptoms further supported the pathogenicity of this variant and its autosomal recessive inheritance. Runs of homozygosity (ROH) analysis indicated a possible founder effect in the Chuvash population. Our study expands the phenotypic spectrum of RINT1-related ILFS3, which in this case lacked the skeletal or neurological features previously described but included neutropenia.
CONCLUSION: We report a novel RINT1 variant cause ILFS3 and neutropenia, supporting its classification as a potential population-specific disorder. These findings highlight the importance of early genetic screening and clinical monitoring in affected populations.
PMID:41057908 | DOI:10.1186/s40246-025-00827-5
