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

Yan, Yousheng; Zhang, Chuan; Jin, Xiaohua; Zhang, Qinhua; Zheng, Lei; Feng, Xuan; Shen, Hao; Gao, Huafang; Ma, Xu

doi:10.1007/s11011-019-0387-7

Cited by 17 publications

(22 citation statements)

References 21 publications

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“…This might be due to the higher frequency of the p.Arg53His variant in this region. Finally, the p.Phe392Ile variant was only observed in patients with MHP, in line with the results of previous studies [3,17].…”

Section: Discussionsupporting

confidence: 92%

“…The variants p.Arg53His and p.Phe392Ile had a higher frequency in MPH patients (P = 0.001 and 0.014, respectively), while p.Arg241Cys and p.Arg408Gln had a higher frequency in mPKU patients. In addition, p.Arg53His variant was more frequent MHP patients, in line with the results of previous large-sample studies [3,17]. In vitro studies have reported that the residual activity of the p.Arg53His-type PAH enzyme was equivalent to 79% of that of the wild-type [12,24].…”

Section: Discussionsupporting

confidence: 89%

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Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

Zhou

Luo

Zeng

et al. 2021

Preprint

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Phenylalanine hydroxylase deficiency (PAHD) is the most prevalent inborn error of amino acid metabolism in China, has a complex phenotype with many variants and genotypes among different populations. Here, we analyzed the phenylalanine hydroxylase（ PAH ） gene mutations in a cohort of 93 PAHD patients from Fujian Province. And, the analysis of genotype and phenotype correlation in patients with PAHD was also determined. 44 different pathogenic variants were identified, including five novel variants. The three most prevalent mutations among all patents were p.Arg53His (18.03%), p.Arg241Cys (14.75%), and p.Arg243Gln (7.65%). The frequency of the p.Arg53His variant was the highest in patients with mild hyperphenylalaninemia (MHP), while the frequency of the p.Val399= and p.Arg111Ter variants was the highest in patients with classic phenylketonuria(cPKU). The most abundant genotypes observed in PAHD patients were p.Arg53His/p.Arg243Gln, p.Arg53His/p.IVS4-1G>A, and p.Arg53His/p.Arg241Cysp. As for the genotype-phenotype prediction, the APV/GPV system performed well in predicting the actual phenotype, as the overall consistency rate was 85.71% for PAHD patients. In conclusion, we established a PAH gene mutation spectrum in the PAHD patients in Southeastern China. A quantitative correlation analysis between genotype and phenotype severity is helpful for genetic counseling and management.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

Zhou

Luo

Zeng

et al. 2021

Preprint

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“…All selected PKU patients were identified through the Newborn Screening program and were diagnosed as having a classic or moderate PKU according to standard classification criteria (Writing Group For Practice Guidelines For Diagnosis And Treatment Of Genetic Diseases Medical Genetics Branch Of Chinese Medical Association et al, 2020). Tetrahydrobiopterin deficiency was excluded, as described in previous research (Yan et al, 2019).…”

Section: Patientsmentioning

confidence: 99%

“…However, the remaining 55 alleles (5.79%) were unknown types (Y. Yan et al, 2019). We hypothesized that these 55 alleles were deleterious deep intronic variants or SVs in PAH.…”

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confidence: 99%

Identification of novel deep intronic PAH gene variants in patients diagnosed with phenylketonuria

et al. 2021

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Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) gene variants. Previously, 94.21% of variants were identified using Sanger sequencing and multiplex ligation‐dependent probe amplification. To investigate the remaining variants, we performed whole‐genome sequencing for four patients with PKU and unknown genotypes to identify deep intronic or structural variants. We identified three novel heterozygous variants (c.706+368T>C, c.1065+241C>A, and c.1199+502A>T) in a deep PAH gene intron. We detected a c.1199+502A>T variant in 60% (6/10) of PKU patients with genetically undetermined PKU. In silico predictions indicated that the three deep variants may impact splice site selection and result in the inclusion of a pseudo‐exon. A c.1199+502A>T PAH minigene and reverse transcription PCR (RT‐PCR) on blood RNA from a PKU patient with biallelic variants c.1199+502A>T and c.1199G>A confirmed that the c.1199+502A>T variant may strengthen the predicted branch point and leads to the inclusion of a 25‐nt pseudo‐exon in the PAH mRNA. Reverse transcription polymerase chain reaction (RT‐PCR) on the minigene revealed that c.706+368T>C may create an SRSF2 (SC35) binding site via a 313‐nt pseudo‐exon, whereas c.1065+241C>A may produce an 81‐nt pseudo‐exon that strengthens the predicted SRSF1 (SF2/ASF) binding site. These results augment current knowledge of PAH genotypes and show that deep intronic analysis of PAH can genetically diagnose PKU.

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“…Three pathogenic mutations in a proband were detected in two of our probands. One carried c. reported previously [9,10]. The genotype of 3 pathogenic mutations in a patient is not uncommon, for an example, a total 35 PKU patients with this genotype were detected from 796 PKU patients by nextgeneration sequencing [3].…”

Section: Spectrum Of Mutations In Pah Genementioning

confidence: 96%

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

Cited by 17 publications

References 21 publications

Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

Identification of novel deep intronic PAH gene variants in patients diagnosed with phenylketonuria

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

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