Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing

Li, Nana; Jia, Haitao; Liu, Zhen; Tao, Jing; Song, Chen; Li, Xiaohong; Deng, Ying; Jin, Xi; Song, Jiaping; Zhang, Liangtao; Liang, Yu; Wang, Wei; Zhu, Jun

doi:10.1038/srep15769

Cited by 46 publications

(53 citation statements)

References 41 publications

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“…accounted for 33.8% of the mutations, similar to the reports from other regions in China [3][4][5] and from Korea [6]. In contrast in Japan, the most prevalent mutation is R413P [7].…”

Section: Spectrum Of Mutations In Pah Genesupporting

confidence: 84%

Molecular diagnosis of Phenylketonuria in 157 Families and Prenatal Diagnosis of Phenylketonuria

Xiao¹,

Gu²,

Wu³

et al. 2019

Preprint

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Background Phenylketonuria (PKU) is a genetic metabolic disease with a relatively higher incidence, but only a few studies about the prenatal diagnosis of PKU have been reported so far in China. The aim of this study was to characterize the spectrum of mutations in PAH gene in PKU probands and the prenatal diagnosis of PKU in north China.Methods A total of 157 families in which PKU patients had been diagnosed were included in the study. The 13 exons and their flanking sequences of PAH gene were amplified by PCR and sequenced in the probands. If none or only one mutant allele was found in the probands, the sample was subjected to MLPA for large deletions/duplication detection in PAH gene. Prenatal diagnosis was performed for pregnant women in these families.Results Pathogenic mutation in PAH was found in 2 alleles in 148 probands and in one allele in 7 probands, and the mutation was not detected in 2 probands. There were 289 point mutants, 10 frame-shift mutations and 4 large deletions with a total of 80 kinds of mutations. The most prevalent mutations were R243Q (17.2%), EX6-96A>G (8.6%) and V399V (8.0%). We also found a novel mutation of 163_164insATAT. Prenatal diagnosis of 95 families found 21 healthy fetus (20.4%), 52 carriers (50.5%) and 30 patients (29.1%), and the accuracy of prenatal diagnosis was confirmed after birth of the fetuses.Conclusion We present here a spectrum of mutations in PAH gene in PKU patients in north China. Prenatal diagnosis for PKU is useful for PKU families to prevent birth of another PKU case.

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“…accounted for 33.8% of the mutations, similar to the reports from other regions in China [3][4][5] and from Korea [6]. In contrast in Japan, the most prevalent mutation is R413P [7].…”

Section: Spectrum Of Mutations In Pah Genesupporting

confidence: 84%

Molecular diagnosis of Phenylketonuria in 157 Families and Prenatal Diagnosis of Phenylketonuria

Xiao¹,

Gu²,

Wu³

et al. 2019

Preprint

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“…NGS is an advanced method to build the PAH mutation spectrum [7]. The NGS procedures were optimized constantly to ensure the data quality.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact reason behind the specific PAH mutation pattern in this area and in Northern and Western regions of China remains unclear, investigation on PAH mutation spectrum of north Jiangsu can facilitate the diagnosis and prognosis of PKU patients in this region. NGS is an advanced method to build the PAH mutation spectrum [7]. The NGS procedures were optimized constantly to ensure the data quality.…”

Section: Mutations North Jiangsu (%)mentioning

confidence: 99%

“…As one of the best studied genetic disorders, PAH‐deficient PKU involves mutations in the 13 exons and 12 introns as well as the upstream and downstream regulatory regions of PAH gene [6]. More than 900 mutations have been identified in PAH , and recorded in the locus‐specific database (LSD) known as PAH vdb (http://www.biopku.org/pah/) [7]. Constructing PAH mutation spectrum can facilitate the diagnosis of PKU, prediction of patients' clinical manifestations, selection of therapeutic options, and design of individualized therapy.…”

Section: Introductionmentioning

confidence: 99%

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PAH mutation spectrum and correlation with PKU manifestation in north Jiangsu province population

Wang

Jiang

Baocheng

2017

The Kaohsiung J of Med Scie

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Phenylketonuria (PKU) is a common autosomal recessive disorder of phenylalanine metabolism and mainly results a deficiency of phenylalanine hydroxylase gene (PAH). The incidence of various PAH mutations have race and ethnicity differences. We report a spectrum of PAH mutations complied from 35 PKU children who are all Chinese Han population from north Jiangsu in this study. All 13 exons and their flanking intron sequences of PAH were determined by Ion Torrent PGM™ sequencing. The relationship of genotype and phenotype was analyzed based on the sum of the arbitrary value (AV) values of the two alleles. We identified 61 mutations, with a frequency of 87.14%, among 70 alleles of 35 patients. The most prevalent mutations were R243Q (26.23%), R241C (9.84%) and V399V (8.20%). Furthermore, the consistency between prediction of the biochemical phenotype and the observed phenotype was 81.25%, with the highest consistency observed in classic PKU (87.50%). A significant correlation was found between pretreatment levels of phenylalanine and AV sum (r = -0.87, P < 0.05). Finally, our study constructs PAH mutation spectrum by next generation sequencing (NGS), and reveals that the PAH genotypes and biochemical phenotypes were significantly correlated. These offers facilitate the provision of appropriate genetic counseling for PKU patients.

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“…In this study, a total 4 mutations (p.R243Q, p.Y356X, p.V399V and A403V) from the 2 cases were identified in PAH gene. p.R243Q, p.Y356X, p.V399V mutations were previously reported in Asian patients such as China, Japan and Korea, and associated with classic PKU disease [12], [13], [14], [15] while A403V mutation was relatively common in European population and resulted to mild hyperphenylalaninemia [16], [17]. V399V looked silent mutation however it confirmed as disease causing due to splicing errors [18].…”

Section: Discussionmentioning

confidence: 99%

The first Mongolian cases of phenylketonuria in selective screening of inborn errors of metabolism

Purevsuren

Bolormaa

Narantsetseg

et al. 2016

Molecular Genetics and Metabolism Reports

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BackgroundInborn errors of metabolism (IEM) are rare genetic disorders in which a single gene defect causes a clinically significant block in a metabolic pathway. Clinical problems arise due to either accumulation of substrates that are toxic or interfere with normal function, or deficiency of the products that are used to synthesize essential compounds. There is no report of screening results or confirmed cases of IEM in Mongolia. Only pilot study of newborn screening for congenital hypothyroidism was implemented in Mongolia, where the incidence of congenital hypothyroidism is calculated to be 1:3057 in Mongolia.MethodsTwo hundred twenty-three Mongolian patients, who had developmental delay, psychomotor retardation with unknown cause, seizures, hypotonia or liver dysfunction, were studied. Urinary organic acid analysis was performed in all cases using gas chromatography mass spectrometric (GC/MS) analysis. Blood amino acids and acylcarnitines were checked in the patients who had abnormal GC/MS analyses. Mutation analysis was done in the patients, who were suspected having specific inborn errors of metabolism by mass spectrometric analysis.ResultsOne hundred thirty-nine children had normal urinary organic acid analyses. Thirty one had metabolites of valproic acid, 17 had non- or hypoketotic dicarboxylic aciduria, 14 had tyrosiluria, 12 had ketosis, 4 had elevation of lactate and pyruvate, 3 had increased excretion of urinary glycerol or methylmalonic acids, respectively, and 2 had elevation of phenylacetate and phenyllactate. We checked blood amino acids and acylcarnitines in 38 patients, which revealed phenylketonuria (PKU) in 2 patients, and one with suspected citrin deficiency. Mutation analysis in PAH was done in 2 patients with PKU, and previously reported p.R243Q, p.Y356X, p.V399V, p.A403V mutations were detected.DiscussionIn conclusion, these were the first genetically confirmed cases of PKU in Mongolia, and the study suggested that the newborn screening program for PKU was significant because it enabled early treatment dietary restriction, specialized formulas and other medical management for prevention of neurological handicaps in these children.

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Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing

Cited by 46 publications

References 41 publications

Molecular diagnosis of Phenylketonuria in 157 Families and Prenatal Diagnosis of Phenylketonuria

Molecular diagnosis of Phenylketonuria in 157 Families and Prenatal Diagnosis of Phenylketonuria

PAH mutation spectrum and correlation with PKU manifestation in north Jiangsu province population

The first Mongolian cases of phenylketonuria in selective screening of inborn errors of metabolism

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