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

2021 ◽  
Author(s):  
Jinfu Zhou ◽  
Jinying Luo ◽  
Yinglin Zeng ◽  
Xiaolong Qiu ◽  
Qingying Lin ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Gene Mutations ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Southeastern China ◽  
Fujian Province ◽  
Quantitative Correlation ◽  
Pathogenic Variants ◽  
Different Populations ◽  
Pah Gene

Abstract 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.

scholarly journals Prevalence of CYP17A1 gene mutations in 17α-hydroxylase deficiency in the Chinese Han population

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Menglin Wang ◽  
Hao Wang ◽  
Haiying Zhao ◽  
Ling Li ◽  
Min Liu ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Gene Mutations ◽  
Autosomal Recessive Disorder ◽  
Chinese Han ◽  
Hydroxylase Deficiency ◽  
Case Presentation ◽  
Chinese Populations ◽  
Pathogenic Variants ◽  
Cytochrome P450 Family ◽  
Chinese Girls

Abstract Background 17α-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene. The major clinical presentation includes hypertension, hypokalemia, male pseudohermaphroditism and female gonadal dysplasia. Hundreds of pathogenic variants have been reported in this disorder, and some common mutations were found to be race-specific. Case presentation In this study, we reported 5 Chinese girls with 17α-hydroxylase deficiency from Henan Province. The patients all came to the hospital for hypertension, and they also presented with sexual infantilism. The average age of the patients was 14 years old, ranging from 12 to 17 years old. They all had reduced blood cortisol, estradiol (E2), and testosterone (TESTO) and increased adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). They all had the appearance of females; however, three of the chromosome karyotypes were 46XX, and two were 46XY. Conclusions All of the patients carried a mutation on the 329 amino acid of CYP17A1 exon 6. By summarizing the currently known pathogenic mutations of 17α-hydroxylase deficiency, we demonstrated the prevalence of these gene mutations in Chinese Han and non-Chinese populations.

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation

1999 ◽  
Vol 105 (5) ◽  
pp. 468-473 ◽  
Author(s):  
J. Mallolas ◽  
M. Antònia Vilaseca ◽  
J. Campistol ◽  
N. Lambruschini ◽  
F. José Cambra ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Mutational Spectrum ◽  
Genotype Phenotype Correlation

scholarly journals Identifying UGT1A1 gene mutations in Vietnamese patients with Gilbert syndrome

2021 ◽  
Vol 63 (2) ◽  
pp. 16-20
Author(s):  
Thi Thanh Hoa Nguyen ◽  
◽  
Quang Lieu Dau ◽  
Dang Ton Nguyen ◽  
Hai Ha Nguyen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Promoter Region ◽  
Gene Mutations ◽  
Tata Box ◽  
Enzyme Expression ◽  
Ugt1a1 Gene ◽  
Gilbert Syndrome ◽  
Pathogenic Variants ◽  
Bilirubin Metabolism ◽  
Different Populations

Gilbert’s syndrome (GS) is the most common inherited disorder of bilirubin metabolism, non-lethal, affecting 3-12% of the population. The genetic variants of the UDP- glucuronosyltransferase 1A1 (UGT1A1) gene might reduce the gene transcription activity and its enzyme expression, which affects the ability to conjugate glucuronidation in the liver. This study aimed to identify genetic variants of UGT1A1 in two Vietnamese sibling brothers with jaundice manifestations suspected GS. The peripheral blood samples of patients were used to extract genome DNA and sequence the enhancer, promoter, and coding all five exons of UGT1A1. Two pathogenic variants c.-3279T>G located in the phenobarbital responsive enhancer module (gtPBREM) and A(TA)7TAA of the TATA box in the promoter region were identified. They are twice common pathogenic variants that were reported in almost hyperbilirubinemia individuals from different populations. The obtained results improved the accuracy of medical diagnosis and warned the patients to be cautious in case they have to use medical drugs in the future.

scholarly journals IDENTIFICATION OF MUTATIONS IN THE PAH GENE IN PKU PATIENTS IN THE STATE OF MATO GROSSO

2020 ◽  
Vol 38 ◽  
Author(s):  
Roseli Divino Costa ◽  
Bianca Borsatto Galera ◽  
Bianca Costa Rezende ◽  
Amanda Cristina Venâncio ◽  
Marcial Francis Galera
Keyword(s):  
Newborn Screening ◽  
Phenylalanine Hydroxylase ◽  
Frequent Mutation ◽  
Screening Service ◽  
Phenotype Correlation ◽  
Salting Out ◽  
Cross Sectional ◽  
Mato Grosso ◽  
Genotype Phenotype Correlation ◽  
Pah Gene

ABSTRACT Objective: To identify phenylalanine hydroxylase (PAH) mutations in patients with phenylketonuria (PKU) from the Newborn Screening Service in Mato Grosso, Midwest Brazil. Methods: This is a cross-sectional descriptive study. The sample consisted of 19 PKU patients diagnosed by newborn screening. Molecular analysis: DNA extraction using the “salting-out” method. Detection of IVS10nt-11G>A, V388M, R261Q, R261X, R252W, and R408W mutations by the restriction fragment length polymorphism (RFLP) technique. Results: Two mutant alleles were identified in four patients (21.1%), one allele in five patients (26.2%), and none in the remaining ten patients (52.6%). A total of 13/38 alleles were detected, corresponding to 34.2% of the PAH alleles present. The most prevalent variant was V388M (13.2% of the alleles), followed by R261Q (10.1%) and IVS10nt-11G>A (7.9%). Three variants (R261X, R252W, and R408W) were not found. The most frequent mutation types were: missense mutation in eight alleles (18.4%) and splicing in four alleles (10.5%). The model proposed by Guldberg to determine a genotype/phenotype correlation was applied to four classical PKU patients with two identified mutations. In three of them, the predicted moderate/moderate or moderate PKU phenotype did not coincide with the actual diagnosis. The prediction coincided with the diagnosis of one classic PKU patient. The estimated incidence of PKU for Mato Grosso, Brazil, was 1:33,342 live births from 2003 to 2015. Conclusion: The only mutations found in the analyzed samples were the IVS10nt-11G>A, V388M, and R261Q. The genotype/phenotype correlation only occurred in four (5.3%) patients.

scholarly journals QuantStudio 12k flex Real-Time PCR system for screening phenylalanine hydroxylase (PAH) gene mutations

2020 ◽  
pp. 71-72
Author(s):  
О.В. Курилова ◽  
М.В. Климушина ◽  
А.В. Киселева ◽  
О.П. Скирко ◽  
Е.А. Сотникова ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
High Frequency ◽  
Phenylalanine Hydroxylase ◽  
Gene Mutations ◽  
Population Based ◽  
Gene Variants ◽  
Heterozygous Carriers ◽  
Custom Panel ◽  
Pah Gene

Целью работы было создание и апробация панели из 23 мутаций гена PAH, ответственных за развитие фенилкетонурии, и оценка частоты гетерозиготного носительства данных мутаций в популяционной выборке ЭССЕ-Вологда. Исследование включало 642 участника из популяционной выборки региона Вологды. Наличие мутаций в гене PAH определяли с помощью системы QuantStudio 12K Flex Real-Time PCR. Среди 642 участников исследования было выявлено 17 носителей мутаций в гене PAH. Частота гетерозиготных мутаций составила 2,65% (ДИ 95%: 1,55--4,21%) или 1:38 человек. Полученные данные свидетельствуют о высокой частоте носительства мутаций гена PAH в российской популяции. Предложенная панель может быть использована для скрининга носительства мутаций, вызывающих фенилкетонурию. The aim of the work was to create and test a custom panel of 23 PAH gene variants responsible for the development of phenylketonuria, and to evaluate the frequency of heterozygous carriers of these mutations among 642 participants of the population-based cohort study ESSE-Vologda. The presence of mutations was determined using QuantStudio 12K Flex Real-Time PCR system. 17 carriers of PAH variants among 642 participants were identified. The frequency of heterozygous carriers was 2.65% (CI95%: 1.55-4.21%), or 1:38. The data obtained indicate a high frequency of PAH variants in the Russian population. The proposed panel can be used for screening on heterozygous carriers of variants that cause phenylketonuria.

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation

1999 ◽  
Vol 105 (5) ◽  
pp. 468-473 ◽  
Author(s):  
J. Mallolas ◽  
M. Antònia Vilaseca ◽  
J. Campistol ◽  
N. Lambruschini ◽  
F. José Cambra ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Mutational Spectrum ◽  
Genotype Phenotype Correlation

CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

2019 ◽  
Vol 91 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Rita Santos-Silva ◽  
Rita Cardoso ◽  
Lurdes Lopes ◽  
Marcelo Fonseca ◽  
Filipa Espada ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Pediatric Endocrinology ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Salt Wasting ◽  
Large Deletions ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype–phenotype correlation. Methods: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype–phenotype correlation. Results: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients’ stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype–phenotype correlation (80%). Conclusion: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype–phenotype correlation observed.

scholarly journals Myocilin gene mutations: A cause of juvenile open-angle glaucoma in north India

2021 ◽  
Author(s):  
Manoj Yadav ◽  
Anupama Deora ◽  
Sumit Sachdeva ◽  
Manisha Rathi ◽  
Jitender Phogat ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Early Adulthood ◽  
Gene Mutations ◽  
North India ◽  
Specific Information ◽  
Open Angle ◽  
Pathogenic Variants ◽  
Different Populations

Abstract Purpose Juvenile-onset open-angle glaucoma (JOAG) is an uncommon type of primary open-angle glaucoma that affects individuals during childhood and early adulthood. Pathogenic variants in the myocilin gene account for varying frequencies of primary open-angle glaucoma and JOAG cases in different populations. This study has screened and identified novel and previously identified myocilin variants in a north Indian cohort of JOAG patients. Methods Eighty unrelated JOAG cases and one hundred controls have been screened for MYOC variants by PCR and DNA sequencing of exons. Results DNA sequencing revealed seventeen different variants. Out of these variants, five (p.G122A, p.R136I, p.S173T, p.K216I, and p.R200KTer*15) were novel and registered in NCBI. Pathogenic MYOC variants identified in 7.5% of JOAG cases. Conclusion Pathogenic myocilin variants account for 7.5% of cases of JOAG in our patient’s cohort. This study augments the mutation spectrum of the MYOC gene, provides population-specific information, and aids in better understanding the underlying lesions of the disease.

scholarly journals Development of a mutation hotspot detection kit for the phenylalanine hydroxylase gene by ARMS-PCR combined with fluorescent probe technology

2021 ◽  
Vol 41 (2) ◽  
Author(s):  
Rong Qiang ◽  
Lin Wang ◽  
JinHua He ◽  
Wei Jie Xu ◽  
Wei Li ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
Mutation Frequency ◽  
Phenylalanine Hydroxylase ◽  
Gene Mutations ◽  
Shaanxi Province ◽  
Amplification Refractory Mutation System ◽  
Missense Mutations ◽  
Hotspot Detection ◽  
Arms Pcr ◽  
Pah Gene

Abstract To develop a screening kit for detecting mutation hotspots of the phenylalanine hydroxylase (PAH) gene. Thirteen exons of the PAH gene were sequenced in 84 cases with phenylketonuria (PKU) diagnosed during neonatal genetic and metabolic disease screening in Shaanxi province, and their mutations were analyzed. We designed and developed a screening kit to detect nine mutation sites covering more than 50% of the PAH mutations found in Shaanxi province (c.728G>A, c.1197A>T, c.331C>T, c.1068C>A, c.611A>G, c.1238G>C, c.721C>T, c.442-1G>A, and c.158G>A) by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) combined with fluorescent probe technology. Peripheral blood and dried blood samples from PKU families were used for clinical verification of the newly developed kit. PAH gene mutations were detected in 84 children diagnosed with PKU. A total of 159 mutant alleles were identified, consisting of 100 missense mutations, 28 shear mutations, 24 nonsense mutations, and 7 deletion mutations. Exon 7 had the highest mutation frequency (32.08%). Among them, the mutation frequency of p.R243Q was the highest, accounting for 20.13% of all mutations, followed by p.R111X, IVS4-1G>A, EX6-96A>G, and p.R413P; these five loci accounted for 47.17% (75/159) of all mutations. In addition, we identified three previously unreported PAH gene mutations (p.C334X, p.G46D, and p.G256D). Fifteen mutation sites were identified in the 47 PAH carriers identified by next-generation sequencing (NGS), which were verified by the newly developed kit, with an agreement rate of 100%. This newly developed kit based on ARMS-PCR combined with fluorescent probe technology can be used to detect common PAH gene mutations.

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