背景:基因分型预测苯丙氨酸羟化酶(Pah)缺乏症患者的变异表型的价值是一个有争议的问题。然而,没有针对汉族的全面的人口关系研究。
方法:我们分析了338例具有109种不同Pah突变的无关中国患者中186种不同基因型的基因型-表型相关性。在该过程中使用两个系统。第一个是基于归因于每个突变的任意值(AV)的表型预测系统。第二个是成对相关分析。用于AV分析的观察到的表型是根据预处理苯丙氨酸(Phe)值分层的相应代谢表型。
结果:我们发现,在272例可获得AV信息的患者中,有54.41%的患者观察到的表型与预测的表型相匹配;在具有空/空基因型的患者中发现了最高程度的一致性(61.83%),而预期轻度PKU表型的患者的“一致率”最低(32.69%)。R241C等突变存在重复的不一致,R243Q,R261Q,V388M,V399V,R408Q,A434D和EX6-96A>G,其与具有相同基因型的患者的可变表型相关。治疗前Phe值与预测的残留活性(r=-0.45643,P<0.0001)或AV总和(r=-0.59523,P<0.0001)之间存在显着相关性。
结论:我们的研究支持Pah突变基因型是特定人群中大多数患者代谢表型的主要决定因素,并为支持中国PKU后续治疗和预后的价值观提供了新的见解。
BACKGROUND: The value of genotyping to predict variant phenotypes in patients with phenylalanine hydroxylase (Pah) deficiency is a matter of debate. However, there exists no comprehensive population relationship study focused on the Han Chinese.
METHODS: We analyzed genotype-phenotype correlation for 186 different genotypes in 338 unrelated Chinese patients harboring 109 different Pah mutations. Two systems were used in this process. The first was a phenotype prediction system based on arbitrary values (AV) attributed to each mutation. The second was a pair-wise correlation analysis. The observed phenotype for AV analysis was the corresponding metabolic phenotype stratified according to the pretreatment phenylalanine (Phe) value.
RESULTS: We found that the observed phenotype matched the predicted phenotype in 54.41% of 272 patients for whom AV information was available; the highest degree of concordance (61.83%) was found in patients with null/null genotypes, whereas the lowest \"concordance rate\" (32.69%) was observed for patients with expected mild-PKU phenotype. There are repeated inconsistencies for such mutations as R241C, R243Q, R261Q, V388M, V399V, R408Q, A434D and EX6-96A>G which are associated with variable phenotypes in patients with identical genotype. Significant correlations were disclosed between pretreatment Phe values and predicted residual activity (r=-0.45643, P<0.0001) or AV sum (r=-0.59523, P<0.0001).
CONCLUSIONS: Our study supports the notion that the Pah mutation genotype is the main determinant of metabolic phenotype in most patients in a particular population, and provided novel insights into the values that underpin the subsequent treatment and the prognosis of PKU in Chinese.