Identification and Characterization of Novel Variants of Fumarylacetoacetate Hydrolase (FAH) Gene in Clinically Suspected Patients of Tyrosinemia Type 1: Tertiary Care Centre Study of North India.

Abstract

Tyrosinemia type I is a rare autosomal recessive metabolic disease caused by the deficiency of Fumarylacetoacetate hydrolase (FAH). The deficiency leads to the accumulation of toxic metabolites leading to the hepatorenal complications. The present study was planned for the identification of the spectrum of disease-causing mutations in the FAH gene of North Indian population. 70 clinically suspected tyrosinemia type I patients were recruited. Urinary Succinylacetone was estimated using Gas Chromatography Mass spectrometry (GCMS). The gene FAH was sequenced by Sanger sequencing in the patients whose exons showed band mobility change by single standard conformation polymorphism (SSCP) screening. Identified variants were functionally analyzed using insilico software tools for identification of pathogenic variants with in vitro functional characterization. Urinary Succinylacetone was not detected in urine of the recruited patients. Sequencing analysis revealed 24variants in nine patients. The majority of these variants were predicted to be disease causing by in silico software programs. In vitro, analysis showed that variants L17P + F22I + I373T and G307X, S130C and G307X can reduce protein expression and catalytic activity of FAH. Tyrosinemia type I is a rare disease but has severe mortality and morbidity. In India, diagnostic and treatment strategies are insufficient against this disease; therefore, majority of the cases may remain undiagnosed. Identification of these disease-causing mutations in the recruited study subjects implicate the requirement of neonatal or prenatal screening for Tyrosinemia Type I in future.

Supplementary information: The online version contains supplementary material available at 10.1007/s12291-024-01236-6.