Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Sci Rep. 2018 Nov 20;8(1):17137. doi: 10.1038/s41598-018-35373-9.
Phenylalanine hydroxylase deficiency (PAHD), one of the genetic disorders resulting in hyperphenylalaninemia, has a complex phenotype with many variants and genotypes among different populations. Here, we describe the mutational and phenotypic spectrum of PAHD in a cohort of 420 patients from neonatal screening between 1999 and 2016. The observed phenotypes comprised 43.57% classic phenylketonuria, 33.10% mild PKU, and 23.33% mild hyperphenylalaninemia, with an overall PAHD incidence of 1 in 20,445. Genetic testing was performed for 209 patients and 72 variants including seven novel variants were identified. These included two synonymous and five pathogenic nonsynonymous variants (p.S36*, p.T186I, p.L255W, p.F302V and p.R413H). The most common variant among all patients was p.R243Q, followed by p.R241C, p.Y204C, p.R111* and c.442-1G > A. Variants p.R53H and p.F392I occurred only in MHP with 19.3% and 8.0% of the observed alleles respectively. The genotypes p.[R241C];[R243Q], p.[R243Q];[R243Q], and p.[Y204C];[R243Q] were abundant across all PAHD patients. The distributions of the null allele and the three defined genotypes, null/null, null/missense, and missense/missense, were significantly different between the cPKU and mPKU patients. However, no significant differences were found between mPKU and MHP patients, indicating that other modifier factors influence the phenotypic outcome in these patients. The data presented here will provide a valuable tool for improved genetic counseling and management of future cases of PAHD in China.
苯丙氨酸羟化酶缺乏症（PAHD）是导致高苯丙氨酸血症的遗传疾病之一，在不同人群中具有复杂的表型，存在许多变异体和基因型。在这里，我们描述了 1999 年至 2016 年间新生儿筛查队列中 420 例患者的 PAHD 突变和表型谱。观察到的表型包括 43.57%的经典苯丙酮尿症、33.10%的轻度苯丙酮尿症和 23.33%的轻度高苯丙氨酸血症，PAHD 的总发病率为每 20445 例 1 例。对 209 例患者进行了基因检测，发现了 72 种变异体，包括 7 种新的变异体。其中包括两个同义变异体和五个致病性非同义变异体（p.S36*、p.T186I、p.L255W、p.F302V 和 p.R413H）。所有患者中最常见的变异体是 p.R243Q，其次是 p.R241C、p.Y204C、p.R111*和 c.442-1G > A。变异体 p.R53H 和 p.F392I 仅在 MHP 中出现，其等位基因分别占观察到的等位基因的 19.3%和 8.0%。基因型 p.[R241C];[R243Q]、p.[R243Q];[R243Q]和 p.[Y204C];[R243Q]在所有 PAHD 患者中均大量存在。纯合缺失/缺失、杂合缺失/错义、纯合错义/错义三种基因型在 cPKU 和 mPKU 患者中的分布有显著差异。然而，mPKU 和 MHP 患者之间没有发现显著差异，表明其他修饰因子影响这些患者的表型结果。本研究提供的资料将为中国未来 PAHD 病例的遗传咨询和管理提供有价值的工具。
