Identification and functional characterization of a novel homozygous intronic variant in the fumarylacetoacetate hydrolase gene in a Chinese patient with tyrosinemia type 1

Background Hereditary tyrosinemia type 1 (HT1; OMIM# 276700) is a genetic metabolism disorder caused by disease-causing variants in the fumarylacetoacetate hydrolase ( FAH ) gene encoding the last enzyme of the tyrosine catabolic pathway. Herein, we describe the clinical features and genetic characteristics of HT1 in a five years and seven months old Chinese patient. Methods After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis. Results We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods. Conclusions Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned.