Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

Zhou, Jinfu; Zeng, Yanli; Qiu, Xiao‐Long; Lin, Qingying; Chen, Weifeng; Luo, Jiafa; Xu, Liangpu

doi:10.1007/s11033-022-07579-8

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…In addition, the highest frequency of PAH variant in Hainan province was c.611A > G ( Zhao et al, 2020 ), which was also a common variant in Jiangxi province. There are considerable differences in common variants of different countries and provinces ( Liu et al, 2017 ; Zhou et al, 2022 ). The low incidence and differences of common variants indicated that the concentrated distribution of PAH gene variants in Jiangxi province was less obvious, which was a challenge for genetic counseling.…”

Section: Discussionmentioning

confidence: 99%

Screening and mutation analysis of phenylalanine hydroxylase deficiency in newborns from Jiangxi province

et al. 2023

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Background: Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive disorder of amino acid metabolism and caused by mutations in the phenylalanine hydroxylase (PAH) gene. Without timely and appropriate dietary management, the disturbance of amino acid metabolism may impair cognitive development and neurophysiological function. Newborn screening (NBS) can aid the early diagnosis of PAHD, which can give accurate therapy to PAHD patients in time. In China, the PAHD incidence and PAH mutation spectrum vary enormously across the provinces. A total of 5,541,627 newborns from Jiangxi province were screened by NBS between 1997 and 2021.Method: One seventy one newborns from Jiangxi province were diagnosed with PAHD. By Sanger sequencing and the multiplex ligation-dependent probe amplification (MLPA) analysis, mutation analysis was performed in 123 PAHD patients. Using an arbitrary values (AV)-based model, we compared the observed phenotype with the predicted phenotype based on the genotype.Results: In this study, we speculated the PAHD incidence of Jiangxi province was about 30.9 per 1,000,000 live births (171/5,541,627). We summarized the PAH mutation spectrum in Jiangxi province for the first time. Two novel variants (c.433G > C, c.706 + 2T > A) were found. The most prevalent variant was c.728G > A (14.1%). The overall prediction rate of the genotype-phenotype was 77.4%.Conclusion: This mutation spectrum is very meaningful to improve the diagnostic rate of PAHD and to increase the accuracy genetic counseling. This study offers data for the genotype-phenotype prediction suitable for Chinese population.

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Section: Discussionmentioning

confidence: 99%

Screening and mutation analysis of phenylalanine hydroxylase deficiency in newborns from Jiangxi province

et al. 2023

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“…The NBS workflow was based on a previously described procedure ( Zhou et al, 2022 ). In brief, dried blood spot (DBS) samples were collected and transported via a cold-chain transportation system to the corresponding NBS center.…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA was isolated from DBS samples using a QIAamp DNA Mini Kit (Tiangen Biotech, China) according to the manufacturer’s instructions. Targeted next-generation sequencing was used to detect a target sequencing panel of 94 genes (including PAH , PTS , GCH1 , QDPR , and PCBD1 ) related to inborn metabolic errors for the patients and their parents using the Biosan (Zhejiang, China) platform, as describedin a previous study ( Zhou et al, 2022 ). Genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines ( https://clinicalgenome.org ).…”

Section: Methodsmentioning

confidence: 99%

Biochemical and molecular features of tetrahydrobiopterin deficiency in Fujian Province, southeastern China

Qiu

Zhao

et al. 2023

Front. Genet.

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The estimated prevalence of tetrahydrobiopterin deficiency (BH4D) and the mutational spectrum of the causal 6-pyruvoyl-tetrahydropterin synthase (PTS) gene vary widely according to race and region. This study assessed the prevalence and genetic characteristics of BH4D in Fujian Province, southeastern China. A total of 3,204,067 newborns were screened between 2012 and 2022 based on the phenylalanine level and the phenylalanine/tyrosine ratio in dried blood spots. Differential diagnosis was determined by the urine purine spectrum, dihydropteridine reductase activity in red blood cells, and genetic testing. The PTS mutation spectrum and genotypes were determined by next-generation sequencing. A total of 189 newborns were diagnosed with hyperphenylalaninemia (HPA) over the study period, including 159 with phenylalanine hydroxylase deficiency and 30 with BH4D. Therefore, the prevalence of BH4D in Fujian was 9.36 per 1,000,000 live births (30/3,204,067) and the proportion of BH4D among patients with HPA was 15.87% (30/189). A total of 58 PTS alleles were identified in the 29 patients with PTS deficiency (PTPSD), and those alleles were composed of 10 different variants, including eight missense variants and two splice-site variants. The most prevalent variants were c.155A>G, p.Asn52Ser (44.83%); c.259C>T, p.Pro87Ser (39.66%); and c.84-291A>G, p.Tyr27Argfs*8 (3.45%). The predominant genotype was c [155A>G]; [259C>T] (11/29, 37.93%). The prevalence of BH4D and the spectrum of associated PTS mutations were successfully determined for the first time in Fujian Province, southeastern China. Since the mutation spectrum of PTS is region-specific, such data will facilitate molecular diagnosis and genetic counseling in PTPSD cases.

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“…Genomic DNA was isolated from DBS using a QIAamp DNA Mini Kit (Tiangen Biotech, China) according to the manufacturer’s instructions. Target next-generation sequencing was performed to detect a target sequencing panel of 94 genes (including GCDH ) related to inborn metabolic errors, as previously described [ 37 ]. Briefly, the target region sequences were enriched and purified.…”

Section: Methodsmentioning

confidence: 99%

Biochemical and molecular features of chinese patients with glutaric acidemia type 1 from Fujian Province, southeastern China

Lin

Zhao

et al. 2023

Orphanet J Rare Dis

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Background Glutaric acidemia type 1 (GA1) is a rare autosomal recessive inherited metabolic disorder caused by variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). The estimated prevalence of GA1 and the mutational spectrum of the GCDH gene vary widely according to race and region. The aim of this study was to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 in Fujian Province, southeastern China. Results From January 2014 to December 2022, a total of 1,151,069 newborns (631,016 males and 520,053 females) were screened using MS/MS in six newborn screening (NBS) centers in Fujian Province and recruited for this study. Through NBS, 18 newborns (13 females and 5 males) were diagnosed with GA1. Thus, the estimated incidence of GA1 was 1 in 63,948 newborns in Fujian province. In addition, 17 patients with GA1 were recruited after clinical diagnosis. All but one patient with GA1 had a remarkable increase in glutarylcarnitine (C5DC) concentrations. The results of urinary organic acid analyses in 33 patients showed that the concentration of glutaric acid (GA) increased in all patients. The levels of C5DC and GA in patients identified via NBS were higher than those in patients identified via clinical diagnosis (P < 0.05). A total of 71 variants of 70 alleles were detected in patients with GA1, with 19 different pathogenic variants identified. The three most prevalent variants represented 73.23% of the total and were c.1244-2 A > C, p.(?) (63.38%), c.1261G > A, p.Ala421Thr (5.63%), and c.406G > T, p.Gly136Cys (4.22%). The most abundant genotype observed was c.[1244-2 A > C]; [1244-2 A > C] (18/35, 52.43%) and its phenotype corresponded to high excretors (HE, GA > 100 mmol/mol Cr). Conclusions In conclusion, we investigated the biochemical and molecular features of 35 unrelated patients with GA1. C5DC concentrations in dried blood spots and urinary GA are effective indicators for a GA1 diagnosis. Our study also identified a GCDH variant spectrum in patients with GA1 from Fujian Province, southeastern China. Correlation analysis between genotypes and phenotypes provides preliminary and valuable information for genetic counseling and management.

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Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

Cited by 6 publications

References 39 publications

Screening and mutation analysis of phenylalanine hydroxylase deficiency in newborns from Jiangxi province

Screening and mutation analysis of phenylalanine hydroxylase deficiency in newborns from Jiangxi province

Biochemical and molecular features of tetrahydrobiopterin deficiency in Fujian Province, southeastern China

Biochemical and molecular features of chinese patients with glutaric acidemia type 1 from Fujian Province, southeastern China

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