Estimation of hereditary fructose intolerance prevalence in Chinese population

Abstract Background: Hereditary fructose intolerance (HFI) caused by aldolase B (ALDOB) reduction or deficiency is a rare inherited autosomal recessive (AR) disease that results in fructose metabolism disorder. The disease prevalence in the Chinese population is unknown, which leads to the lack of basis for the formulation of HFI screening and diagnosis strategy. Materials & Methods: From searching local cohort (Chinese Children’s Rare Disease Genetic Testing Clinical Collaboration System, CCGT), public databases (ClinVar and HGMD) and reviewing HFI-related literature (PubMed and Web of Science), we manually curated ALDOB pathogenic or likely-pathogenic (P/LP) variants according to ACMG guidelines. Allele frequency (AF) information from local CCGT, HuaBiao, and gnomAD database for ALDOB P/LP variants were used to estimate and the HFI prevalence in Chinese and other populations by the Bayesian framework. We collected the genotype and clinical characteristics of HFI patients from the CCGT database and published literature to study genotype-phenotype relationships. Result: In total 81 variants from ALDOB were curated as P/LP. The estimated Chinses HFI prevalence is approximately 1/504,678, which is similar to gnomAD-AFR (1/412,335) and SAS (1/465,278) population and much lower than NFE (1/23,147), FlN (1/55,539), AMR (1/132,801) and ASJ (1/263,150) populations. By analyzing the genetic characteristics of ALDOB in Chinese population, two variants (A338V, A338G) had significantly higher AF in Chinese population by comparing to NFE populations from gnomAD (all P-value<0.05). Five variants (A150P, A175D, N335K, R60*, R304Q) had significantly lower AF (all P-value<0.1). The results of genotype-phenotype association showed that patient carrying homozygous variant sites (especially A150P) were more likely to present nausea, and patient carrying two missense variant sites were more likely to present aversion to sweets and fruit (all P-value<0.05). Our research reveals that some gastrointestinal symptoms seem to be associated with genotypes.Conclusion: Chinese population had extremely low prevalence of HFI, with no need to add in current newborn screening project if consider medical costs. Genetic test strategy was suggested for early diagnoses.