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The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

ABSTRACT: Background:Neonatal hyperphenylalaninemia (HPA) screening did not begin until 2009 in the Uygur population because of poor medical and economic conditions. This study intended to investigate HPA incidence rate and characterize mutation spectrum of phenylalanine hydroxylase (PAH) gene within the Uygur population. Methods:Cross-sectional data of National Direct Reporting System database from 2009 to 2016 were used to calculate incidence rate. All HPA positive newborns were diagnosed and confirmed by Sanger sequencing. A low Phe diet was implemented. Results:A total of 580,608 Uygur neonates were screened, 111 were diagnosed with HPA with an incidence rate of 1:5,230, 58 different mutations in PAH gene were detected. Eight novel variants were found, including two nonsense mutations (L11*, L197*), two splicing mutations (IVS12-2A > C, IVS13-1G > A), one frameshift mutation (K115 > Hfs) and three missense mutations (E368K, E370G, D435V), distributing in twenty patients. A104D was the most frequent mutation in this study, and the other hot spot of R413P was found in 4 patients in a same Uygur village with a carrier rate of 1:2.1. Conclusions:This is the first study to investigate HPA incidence rate in the Uygur population. Our study highlights regional differences in PAH genotypes and mutation rates.

SUBMITTER: Su Y

PROVIDER: S-EPMC6614323 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

Su Yajie Y Wang Huijun H Rejiafu Nuerya N Wu Bingbing B Jiang Haili H Chen Hongbo H A Xian X Qian Yanyan Y Li Mingzhu M Lu Yulan Y Ren Yan Y Li Long L Zhou Wenhao W

Annals of translational medicine 20190601 12

<h4>Background</h4>Neonatal hyperphenylalaninemia (HPA) screening did not begin until 2009 in the Uygur population because of poor medical and economic conditions. This study intended to investigate HPA incidence rate and characterize mutation spectrum of phenylalanine hydroxylase (<i>PAH</i>) gene within the Uygur population.<h4>Methods</h4>Cross-sectional data of National Direct Reporting System database from 2009 to 2016 were used to calculate incidence rate. All HPA positive newborns were di ...[more]

PMID: 31355225

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Project description:The classic phenotype of Fabry disease, X-linked alpha -galactosidase A (alpha -Gal A) deficiency, has an estimated incidence of approximately 1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the alpha-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and "doubly screened-positive" infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient alpha-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5(+1G-->T)) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an alpha-Gal A-specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of alpha-Gal A deficiency was 1 in approximately 3,100, with an 11 : 1 ratio of patients with the later-onset : classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in approximately 4,600, with a 7 : 1 ratio of patients with the later-onset : classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed--in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders.

Dataset Information

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

Publications

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

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