Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria
Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria
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DOI：
10.1038/s41436-018-0081-x
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发表时间：
2019-03-01
影响因子：
8.8
通讯作者：
Blau, Nenad
中科院分区：
文献类型：
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作者：
Garbade, Sven F.;Shen, Nan;Blau, Nenad
目的：苯丙氨酸羟化酶(PAH)变异的性质决定了残留酶的活性，从而改变了苯丙酮尿症(PKU)的临床表型。方法：采用等位基因表型值(APV)算法对9336例PKU患者的2589种不同基因型、588个变异进行分析。结果：在PAH功能正常的偏侧患者中，共鉴定出251个编码非活性PAH的0变异，并将APV(0=经典PKU；5=轻度PKU；10=轻度高苯丙氨酸血症)分配给88个变异。将基因表型值(GPV)设为APV较高的等位基因，即APV较低的等位基因为显性等位基因，以确定代谢表型。8872例患者的GPV结果显示，典型PKU的界值为0.0~2.7，轻度PKU的界值为2.8~6.6，轻度高苯丙氨酸血症的界值为6.7~10.0。典型PKU、轻度PKU和轻度高苯丙氨酸血症的表型预测值分别为99.2%、46.2%和89.5%。已知的治疗前血苯丙氨酸水平与GPV(n=4217)以及四氢生物蝶呤反应性与GPV(n=3488)之间的关系均有显著意义(P均<0.001)。结论：APV和GPV是研究基因-表型关联的有力工具，可用于PKU家族的遗传咨询。
Purpose: The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU.Methods: A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm.Results: We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001).Conclusions: APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families.