The mutation spectrum and ethnic distribution of non-hepatorenal tyrosinemia (types II, III)

BACKGROUND: Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by pathogenic variants in the tyrosine aminotransferase (TAT), and 4-hydroxyphenyl-pyruvate dioxygenas (HPPD) genes, respectively. There are still unclarified aspects in their clinical presentations, mutational spectrum, and genotype–phenotype correlation. MAIN BODY: In this study, we evaluated the spectrum of TAT and HHPD gene mutations in patients with tyrosinemia type II and III. Moreover, biochemical and clinical findings are evaluated to establish a genotype–phenotype relationship in the above-mentioned patients. Thirty-three TAT variants have been reported in 42 families, consisting of 21 missense variants, 5 frameshift variants, 4 nonsense variants, 2 variants that primarily cause splicing site, and 1 skipping complete exon (large deletion). The most common variant is p.Arg57Ter, causing a splicing defect, and resulting in premature termination of translation, which was found in 10 patients from 3 families. In HPPD gene, eleven variants in 16 patients have been reported including 7 missense variants, 2 nonsense variants, 1 splice defect, and 1 frameshift variant so far. All variants are unique, except for p.Tyr160Cys, which is a missense variant found in two different patients. Regarding genotype–phenotype correlations, in 90% of tyrosinemia type II patients, positive clinical and biochemical correlations with a detected variant are observed. In HPPD gene, due to the small number of patients, it is not possible to make a definite conclusion. CONCLUSION: This is the first large review of variants in TAT and HPPD, highlighting the wide spectrum of disease-causing mutations. Such information is beneficial for the establishment of a privileged mutation screening process in a specific region or ethnic group. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02579-0.