Case Report: Type II tyrosinemia caused by mutations at the c.843_844 inv p.(Trp282Gly) variant locus

ObjectiveTo identify the genetic etiology in a neonate with persistent hypertyrosinemia and characterize the functional impact of a novel TAT gene variant, c.843_844inv.MethodsA neonate suspected of having tyrosinemia type II following newborn screening by tandem mass spectrometry was recruited, along with family members. Whole-exome sequencing (WES) was performed to identify causative variants. To validate the pathogenicity of the identified novel locus, wild-type and mutant TAT expression vectors were constructed. These vectors were transfected into 293T cells to assess mRNA and protein expression levels in vitro. Structural modeling was also employed to predict the impact of the variant on protein stability.ResultsThe proband exhibited persistently elevated blood tyrosine levels (>600 μmol/L) on repeated screenings. Genetic analysis revealed compound heterozygous variants in the TAT gene: a known pathogenic splice-site variant, c.1125 + 1G>T (maternal), and a novel variant, c.843_844inv (p. (Trp282Gly)) (paternal). The proband’s healthy sister carried only the c.843_844inv variant. In vitro functional assays demonstrated that while TAT mRNA levels were unaffected, the p. (Trp282Gly) mutation significantly reduced TAT protein expression to approximately 20.7% of wild-type levels. Structural modeling suggested that the p. (Trp282Gly) substitution disrupts critical hydrogen bonds in the enzyme’s core region.ConclusionA novel pathogenic variant, c.843_844inv (p. (Trp282Gly)), was identified in the TAT gene, which, in combination with c.1125 + 1G>T, causes tyrosinemia type II. Functional studies confirmed that this novel variant leads to a significant reduction in TAT protein levels. These findings expand the mutational spectrum of TAT and provide a basis for clinical diagnosis and genetic counseling.