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.

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Background Hereditary fructose intolerance (HFI) caused by aldolase B reduction or deficiency that results in fructose metabolism disorder. The disease prevalence in the Chinese population is unknown, which impedes the formulation of HFI screening and diagnosis strategies. Materials and methods By searching a local cohort (Chinese Children’s Rare Disease Genetic Testing Clinical Collaboration System, CCGT) and public databases (ClinVar and Human Gene Mutation Database) and reviewing HFI-related literature, we manually curated ALDOB pathogenic or likely pathogenic (P/LP) variants according to ACMG guidelines. Allele frequency (AF) information from the local database CCGT and the public databases HuaBiao and gnomAD for ALDOB P/LP variants was used to estimate and the HFI prevalence in the Chinese population 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 of ALDOB were curated as P/LP. The estimated Chinese HFI prevalence was approximately 1/504,678, which was much lower than that for non-Finland European (1/23,147), Finnish in Finland (1/55,539), admixed American (1/132,801) and Ashkenazi Jewish (1/263,150) populations. By analyzing the genetic characteristics of ALDOB in the Chinese population, two variants (A338V, A338G) had significantly higher AFs in the Chinese population than in the non-Finland European population from gnomAD (all P values < 0.05). Five variants (A150P, A175D, N335K, R60*, R304Q) had significantly lower AFs (all P values < 0.1). The genotype–phenotype association analyses were based on 68 reported HFI patients from a literature review and the CCGT database. The results showed that patients carrying homozygous variant sites (especially A150P) were more likely to present nausea, and patients carrying two missense variant sites were more likely to present aversion to sweets and fruit (all P values < 0.05). Our research reveals that some gastrointestinal symptoms seem to be associated with certain genotypes. Conclusion The prevalence of HFI in the Chinese population is extremely low, and there is no need to add HFI testing to the current newborn screening programs if medical costs are considered. A genetic testing strategy is suggested for early diagnosis of HFI.

Background Fructose-1,6-bisphosphatase deficiency (FBP1D) is a rare inborn error due to mutations in the FBP1 gene. The genetic spectrum of FBP1D in China is unknown, also nonspecific manifestations confuse disease diagnosis. Materials & Methods We collected 101 FBP1 variants from our cohort and public resources, and manually curated pathogenicity of these variants. Ninety-seven pathogenic or likely pathogenic variants were used in our cohort to estimate Chinese FBP1D prevalence by three methods: 1) carrier frequency, 2) permutation and combination, 3) Bayesian framework. Allele frequencies (AFs) of these variants in our cohort, China Metabolic Analytics Project (ChinaMAP) and gnomAD were compared to reveal the different hotspots in Chinese and other populations. Clinical and genetic information of 122 FBP1D patients from our cohort and published literature were collected to analyze the genotype-phenotypes association. Phenotypes of 68 hereditary fructose intolerance (HFI) patients from our previous study were used to compare the phenotypic differences between these two fructose metabolism diseases. Result The estimated Chinese FBP1D prevalence was 1/1,310,034. In the Chinese population, c.490G > A and c.355G > A had significantly higher AFs than in the non-Finland European population, and c.841G > A had significantly lower AF value than in the South Asian population (all P values < 0.05). The genotype-phenotype association analyses showed that patients carrying homozygous c.841G > A were more likely to present increased urinary glycerol, carrying two CNVs (especially homozygous exon1 deletion) were often with hepatic steatosis, carrying two missense variants were not likely to present fever, carrying compound heterozygous variants were usually with lethargy, and carrying homozygous variants were usually with ketosis and hepatic steatosis (all P values < 0.05). By comparing to phenotypes of HFI patients, FBP1D patients were more likely to present hypoglycemia, metabolic acidosis, and seizures (all P value < 0.05). Conclusion The prevalence of FBP1D in the Chinese population is extremely low. Genetic sequencing could effectively help to diagnose FBP1D.