Objective 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. We systematically estimated the FBP1D prevalence in Chinese and explored genotype-phenotype association. 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. Results The estimated Chinese FBP1D prevalence was 1/1,310,034. In the Chinese population, c.490G&amp;gt;A and c.355G&amp;gt;A had significantly higher AFs than in the non-Finland European population, and c.841G&amp;gt;A had significantly lower AF value than in the South Asian population (all p values &amp;lt; 0.05). The genotype-phenotype association analyses showed that patients carrying homozygous c.841G&amp;gt;A were more likely to present increased urinary glycerol, carrying two CNVs (especially homozygous exon1 deletion) were often with hepatic steatosis, carrying compound heterozygous variants were usually with lethargy, and carrying homozygous variants were usually with ketosis and hepatic steatosis (all p values &amp;lt; 0.05). By comparing to phenotypes of HFI patients, FBP1D patients were more likely to present hypoglycemia, metabolic acidosis, and seizures (all p -value &amp;lt; 0.05). Conclusion The prevalence of FBP1D in the Chinese population is extremely low. Genetic sequencing could effectively help to diagnose FBP1D.

Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the Chinese population and analysis of genotype-phenotype association