Molecular Genetics Of Hyperphenylalaninemia In Jiangxi Province

Objective:Hyperphenylalaninemia(HPA)is an amino acid genetic metabolic disorder caused by deficiency of phenylalanine hydroxylase(PAH)or tetrahydrobiopterin(BH4).PAH and BH4 play a key role in the conversion of phenylalanine(Phe)to tyrosine,regulating the rate at which the body metabolizes Phe.HPA is also a preventable and treatable disease,of which newborn screening is an effective way to prevent it.The incidence of HPA and the hotspot mutations of related genes vary greatly in different countries and regions,and it is important to improve the mutation spectrum of PAH gene and PTS gene in each region to improve the quality of the population.In this study,we analyzed HPA-related gene mutations in HPA patients screened and diagnosed in Jiangxi from 2008 to 2022,so as to construct the mutation spectrum of HPA-related genes in Jiangxi and provide an important reference for genetic counseling,prenatal diagnosis and gene therapy of HPA.Methods:1.A total of 191 patients with phenylalanine hydroxylase deficiency(PAHD)were diagnosed at the Newborn Disease Screening Center of Jiangxi Maternal and Child Health Hospital.Sanger sequencing and MLPA analysis were performed on the PAH gene of 130 of these PAHD patients to identify the mutation loci of the patients’ PAH gene,and the corresponding mutation loci of their parents were verified,and the allelic phenotypic value(APV)/genotype Phenotypic value(GPV)model was used to predict the phenotype,and the actual phenotype was compared with the predicted phenotype.2.A total of 74 patients with tetrahydrobiopterin deficiency(BH4D)were diagnosed at the Newborn Disease Screening Center of Jiangxi Maternal and Child Health Hospital.53 of these patients with 6-pyruvoyltetrahydropterin synthase deficiency(PTPSD)had their PTS gene mutation loci identified by Sanger sequencing,and the corresponding mutation loci of their parents were verified.Results:1.The prevalence of PAHD in Jiangxi was 1:30579,and 241 mutant loci and 8large fragment deletions were detected in 130 PAHD patients,containing 82 mutation types,of which R243 Q mutation was the most frequent(33/240,13.25%)and R241 C was the second(15/240,6.02%).2.A total of 93 patients with PAHD were included for APV/GPV genotypephenotype prediction,and their predicted phenotype-actual phenotype concordance reached 76.34%(71/93),including 71.43%(40/56)for classic PKU,70.59%(12/17)for mild PKU,and 95%(19/20)for mild HPA.3.Two new gene mutations,IVS6+2T>A and D145 H,were identified in 130 patients with PAHD.4.The prevalence of BH4 D in Jiangxi region was 1:78919.In 53 patients with PTPSD,106 mutation loci containing 15 mutation types were detected,among which the frequency of P87 S mutation was the highest(47.17%),followed by IVS1-291A>G(19.81%).Conclusion:This study constructed the mutation profiles of PAH gene and PTS gene in Jiangxi,clarified the mutation hotspots of PAH gene and PTS gene,enriched the gene database,laid the foundation for the diagnosis and treatment of HPA patients in Jiangxi,and provided data for genotype-phenotype prediction model.