Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
Department of Neonatology, Children's Hospital of Fudan University, Shanghai, 201102, China.
Orphanet J Rare Dis. 2022 Aug 26;17(1):326. doi: 10.1186/s13023-022-02487-3.
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.
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.
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.
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.
醛缩酶 B 减少或缺乏导致果糖代谢紊乱，引起遗传性果糖不耐受（HFI）。中国人群的疾病流行情况尚不清楚，这阻碍了 HFI 筛查和诊断策略的制定。
通过检索当地队列（中国儿童罕见病基因检测临床协作组，CCGT）和公共数据库（ClinVar 和人类基因突变数据库）以及综述 HFI 相关文献，我们根据 ACMG 指南手动整理了 ALDOB 致病性或可能致病性（P/LP）变异。使用当地数据库 CCGT 和公共数据库 HuaBiao 和 gnomAD 中的等位基因频率（AF）信息，采用贝叶斯框架估计中国人群和其他人群的 HFI 患病率。我们从 CCGT 数据库和已发表文献中收集了 HFI 患者的基因型和临床特征，以研究基因型-表型关系。
共整理了 81 种 ALDOB 的 P/LP 变异。估计中国 HFI 的患病率约为 1/504678，远低于非芬兰裔（1/23147）、芬兰裔（1/55539）、混合裔（1/132801）和阿什肯纳兹犹太人（1/263150）。通过分析中国人群中 ALDOB 的遗传特征，发现两个变异（A338V、A338G）在 gnomAD 中的 AF 明显高于非芬兰裔人群（均 P 值<0.05）。有五个变异（A150P、A175D、N335K、R60*、R304Q）的 AF 明显降低（均 P 值<0.1）。基于文献综述和 CCGT 数据库中 68 例报告的 HFI 患者的基因型-表型关联分析显示，携带纯合变异位点（尤其是 A150P）的患者更易出现恶心，携带两个错义变异位点的患者更易出现厌恶甜食和水果（均 P 值<0.05）。我们的研究表明，一些胃肠道症状似乎与某些基因型有关。
中国人群 HFI 的患病率极低，如果考虑医疗费用，目前无需将 HFI 检测添加到新生儿筛查计划中。建议采用基因检测策略对 HFI 进行早期诊断。
