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Metab Brain Dis. 2019 Feb 12. doi: 10.1007/s11011-019-0387-7. [Epub ahead of print]

Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants.

Yan Y1,2,3, Zhang C3, Jin X1,2, Zhang Q3, Zheng L3, Feng X3, Hao S3, Gao H4,5, Ma X6,7.

Author information

1
Graduate School of Peking Union Medical College, Beijing, 100730, China.
2
National Research Institute for Health and Family Planning, No. 12 Dahuisi Road, Beijing, 100081, China.
3
Gansu Province Medical Genetics Center, Gansu Province Maternal and Child Health Care Hospital, Lanzhou, 730050, China.
4
Graduate School of Peking Union Medical College, Beijing, 100730, China. gaohuafang@nrifp.org.cn.
5
National Research Institute for Health and Family Planning, No. 12 Dahuisi Road, Beijing, 100081, China. gaohuafang@nrifp.org.cn.
6
Graduate School of Peking Union Medical College, Beijing, 100730, China. genetic@263.net.cn.
7
National Research Institute for Health and Family Planning, No. 12 Dahuisi Road, Beijing, 100081, China. genetic@263.net.cn.

Abstract

This study was performed to analyze the mutational spectrum of the phenylalanine hydroxylase (PAH) gene in phenylketonuria (PKU) patients in Northwest China, to identify mutational hot spots, and to determine the correlation between variants and clinical phenotypes of PKU. A large cohort of 475 PKU families in Northwest China was enrolled to analyze PAH gene variants using Sanger sequencing, Multiplex ligation-dependent probe amplification (MLPA), and gap-PCR. Bioinformatics software was used to predict the pathogenicity of novel variants and analyze the correlations between PAH gene variants and phenotypes of PKU patients. A total of 895 variants were detected in the 950 alleles of 475 patients with PKU (detection rate: 94.21%), 20 of which were novel variants. Other 108, previously known variants, were also identified, with the three most frequent variants being p.Arg243Gln (14.00%), c.611A > G (5.58%), and p.Tyr356* (4.95%). Seven different large deletion/duplication variants were identified by the MLPA method, including the large deletion c.-4163_-406del3758 with high frequency. A correlation analysis between patient phenotype and gene variant frequency showed that p.Arg53His and p.Gln419Arg were correlated with mild hyperphenylalaninemia (MHP). In conclusion, the mutational spectrum underlying PKU in Northwest China was established for the first time. Functional analysis of 20 novel PAH gene variants enriched the PAH gene mutational spectrum. Correlation analysis between variants frequencies in compound heterozygous patients and phenotype severity is helpful for phenotypic prediction.

KEYWORDS:

Gap-PCR; Gene variant; MLPA; Phenylalanine hydroxylase; Phenylketonuria; Sanger sequencing

PMID:
30747360
DOI:
10.1007/s11011-019-0387-7

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