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Sci Rep. 2018 Jul 26;8(1):11251. doi: 10.1038/s41598-018-29640-y.

Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China.

Li N1,2, He C1,2, Li J3, Tao J1,2, Liu Z1,2, Zhang C3, Yuan Y4, Jiang H5,6, Zhu J1,2, Deng Y1,2, Guo Y1,2, Li Q2, Yu P7,8, Wang Y9,10.

Author information

1
National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China.
2
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
3
Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China.
4
Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China.
5
BGI-Shenzhen, Shenzhen, 518103, China.
6
China National GeneBank, BGI-Shenzhen, Shenzhen, 518120, China.
7
National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China. yup@scu.edu.cn.
8
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China. yup@scu.edu.cn.
9
National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China. wyxyanping@163.com.
10
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China. wyxyanping@163.com.

Abstract

Mutations in the gene encoding phenylalanine hydroxylase (PAH) are associated with various degrees of phenylketonuria (PKU). The aim of our study was to define the genotype-phenotype correlations of mutations in the PAH gene that cause phenylketonuria (PKU) among the Chinese mainland population. Mutations in the PAH gene were analysed by next-generation sequencing, and a genotype-phenotype correlation analysis was performed in 1079 patients. Fifteen "null + null" genotypes, including four homoallelic and eleven heteroallelic genotypes, were clearly associated with classic PKU. Five functionally hemizygous (p.E280K, p.R252Q, p.E56D, p.S310F and p.T372R) and four compound heterozygous (p.T278I/p.S359L, p.R408W/p.R243Q, p.F161S/p.R243Q and p.F161S/p.R413P) genotypes were clearly associated with classic PKU. Ten functionally hemizygous genotypes, p.G257V, p.R158W, p.L255S, p.G247V, p.F161S, p.R158Q, p.V388M, p.I65T, p.I324N and p.R400K, were frequently associated with classic PKU. Three functionally hemizygous genotypes, p.P147L, p.I95del and p.F331S, and four compound heterozygous genotypes, p.G257V/p.R408Q, p.A434D/p.R413P, p.R243Q/p.A47E and p.R241C/p.G239D, were consistently correlated with mild PKU. Three functionally hemizygous genotypes, p.H107R, p.Q419R and p.F392I, and nine compound heterozygous genotypes (p.G312V/p.R241C, p.R243Q/p.V230I, p.R243Q/p.A403V, p.R243Q/p.Q419R, p.R243Q/p.R53H, p.R243Q/p.H107R, p.R241C/p.R408Q, p.R241C/p.H220P and p.R53H/p.R400K) were consistent with mild hyperphenylalaninaemia (MHP). Our study provides further support for the hypothesis that the PAH genotype is the main factor that determines the phenotype of PKU.

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