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01-10-2015 | Original Article

Mutational spectrum of phenylketonuria in Jiangsu province

Authors: Ya-fen Chen, Hai-tao Jia, Zhong-hai Chen, Jia-ping Song, Yu Liang, Jing-jing Pei, Zhi-jun Wu, Jing Wang, Ya-li Qiu, Gang Liu, Dong-mei Sun, Xin-ye Jiang

Published in: European Journal of Pediatrics | Issue 10/2015

Abstract

Phenylketonuria (PKU) is caused by variants in the phenylalanine hydroxylase (PAH) gene. We systematically investigated all 13 exons of the PAH gene and their flanking introns in 31 unrelated patients and their parents using next-generation sequencing (NGS). A total of 33 different variants were identified in 58 of 62 mutant PAH alleles. The prevalent variants with a relative frequency of 5 % or more were c.721C > T, c.1068C > A, c.611A > G, c.1197A > T, c.728G > A, c.331C > T, and c.442-1G > A. One novel variant was identified in this study—c.699C > G. We studied genotype–phenotype correlations using the Guldberg arbitrary value (AV) system, which revealed a consistency rate of 38 % (8/21) among the 21 predicted phenotypes. The genotype-based prediction of BH4 responsiveness was also evaluated, and 14 patients (45.2 %) were predicted to be BH4 responsive.

Conclusion: This study presents the spectrum of PAH variants in Jiangsu province. The information obtained from the genotype-based prediction of BH4 responsiveness might be used for the rational selection of candidates for BH4 testing.

What is known:

• Phenylketonuria (PKU) is caused by variants in the phenylalanine hydroxylase (PAH) gene.

• The spectrum of PAH variants in different Chinese populations has been reported.

What is new:

• This is the first report on the spectrum of PAH variants in Jiangsu province.

• This study identified one novel PAH variant—c.699C>G—and and tries to show a genotype–phenotype relationship also regarding BH4-responsiveness.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249PubMedCentralCrossRefPubMed

Blau N, Shen N, Carducci C (2014) Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert Rev Mol Diagn 14(6):655–671CrossRefPubMed

Blau N, Yue WW, Perez B. Phenylalanine hydroxylase gene locus-specific database. http://www.biopku.org/home/pah.asp

Blau N, Yue WW, Perez B. BIOPKUdb: database of patients and genotypes causing HPA/PKU incl. BH4-responsive phenotype. http://www.biopku.org/home/biopku.asp

Groselj U, Tansek MZ, Kovac J, Hovnik T, Podkrajsek KT, Battelino T (2012) Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. Mol Genet Metab 106(2):142–148CrossRefPubMed

Guldberg P, Romano V, Ceratto N, Bosco P, Ciuna M, Indelicato A, Mollica F, Meli C, Giovannini M, Riva E, Biasuccl G, Henriksen KF, Güttler F (1993) Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. Hum Mol Genet 2(10):1703–1707CrossRefPubMed

Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63(1):71–79PubMedCentralCrossRefPubMed

Karacić I, Meili D, Sarnavka V, Heintz C, Thöny B, Ramadza DP, Fumić K, Mardesić D, Barić I, Blau N (2009) Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab 97(3):165–171CrossRefPubMed

Karam PE, Alhamra RS, Nemer G, Usta J (2013) Spectrum of mutations in Lebanese patients with phenylalanine hydroxylase deficiency. Gene 515(1):117–122CrossRefPubMed

10.

Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L (2013) Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. Gene 526(2):347–355CrossRefPubMed

11.

Report of birth defects prevention in China (2012) Ministry of Health of the People’s Republic of China http://www.gov.cn/gzdt/2012-09/12/content_2223371.htm

12.

Song F, Qu YJ, Zhang T, Jin YW, Wang H, Zheng XY (2005) Phenylketonuria mutations in Northern China. Mol Genet Metab 86(Suppl 1):S107–S118CrossRefPubMed

13.

Trunzo R, Santacroce R, D'Andrea G, Longo V, De Girolamo G, Dimatteo C, Leccese A, Lillo V, Papadia F, Margaglione M (2013) Mutation analysis in hyperphenylalaninemia patients from South Italy. Clin Biochem 46(18):1896–1898CrossRefPubMed

14.

Vela-Amieva M, Abreu-González M, González-Del Angel A, Ibarra-González I, Fernández-Lainez C, Barrientos-Ríos R, Monroy-Santoyo S, Guillén-López S, Alcántara-Ortigoza MA (2014) Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect. Clin Genet. doi:10.1111/cge.12444 PubMed

15.

Yu WZ, Qiu DH, Song F, Liu L, Liu SM, Jin YW, Zhang YL, Zou HY, He J, Lei Q, Liu XW (2008) Mutation characteristics of the PAH gene in four nationality groups in Xinjiang of China. J Genet 87(3):293–297CrossRefPubMed

16.

Zekanowski C, Nowacka M, Radomyska B, Cabalska B (2001) Should newborn mutation scanning for hyperphenylalaninaemia and galactosaemia be implemented? A Polish experience. J Med Screen 8(3):132–136CrossRefPubMed

17.

Zhou YA, Ma YX, Zhang QB, Gao WH, Liu JP, Yang JP, Zhang GX, Zhang XG, Yu L (2012) Mutations of the phenylalanine hydroxylase gene in patients with phenylketonuria in Shanxi, China. Genet Mol Biol 35(4):709–713PubMedCentralCrossRefPubMed

18.

Zhu T, Qin S, Ye J, Qiu W, Han L, Zhang Y, Gu X (2010) Mutational spectrum of phenylketonuria in the Chinese Han population: a novel insight into the geographic distribution of the common mutations. Pediatr Res 67(3):280–285CrossRefPubMed

19.

Zhu T, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X (2013) Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. Gene 529(1):80–87CrossRefPubMed

20.

Zschocke J, Hoffmann GF (1999) Phenylketonuria mutations in Germany. Hum Genet 104(5):390–398CrossRefPubMed

21.

Zurflüh M, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 29(1):167–175CrossRefPubMed

Title: Mutational spectrum of phenylketonuria in Jiangsu province
Authors: Ya-fen Chen
Hai-tao Jia
Zhong-hai Chen
Jia-ping Song
Yu Liang
Jing-jing Pei
Zhi-jun Wu
Jing Wang
Ya-li Qiu
Gang Liu
Dong-mei Sun
Xin-ye Jiang
Publication date: 01-10-2015
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Pediatrics / Issue 10/2015
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI: https://doi.org/10.1007/s00431-015-2539-z

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Mutational spectrum of phenylketonuria in Jiangsu province

Abstract

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Abstract

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