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.
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Acknowledgements
We would like to thank Professor Shangzhi Huang (from Chinese Academy of Medical Sciences & Peking Union Medical College) for his guidance and precious suggestions of this research, and thank the patients and their families for their participation and valuable blood samples.
Funding
This study was supported by National Key Research and Development Program of China (Grant No.: 2016YFC1000307, and 2018YFC1002201) and Natural Science Foundation of Gansu Province (Grant No.: 1606RJZA151).
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Yan, Y., Zhang, C., Jin, X. et al. Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants. Metab Brain Dis 34, 733–745 (2019). https://doi.org/10.1007/s11011-019-0387-7
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DOI: https://doi.org/10.1007/s11011-019-0387-7