The incidence rate and gene mutation characteristics of hyperphenylalaninemia in Yunnan Province, Southwest China.

backgroundThe global incidence of Hyperphenylalaninemia (HPA) demonstrates significant geographical variations, exhibiting distinct regional and ethnic characteristics in both phenotypic manifestations and genotypic profiles. To date, there remains a paucity of data regarding the genotype-phenotype correlation in pediatric patients with phenylalanine hydroxylase deficiency (PAHD) from Southwest China. This study aims to conduct a retrospective analysis of neonatal HPA prevalence and characterize PAH gene mutations in Yunnan Province in Southwest China. These findings are expected to establish an evidence base for optimizing clinical follow-up protocols, facilitating genetic counseling, and enabling prenatal molecular diagnosis for affected children.

methodsFrom January 2013 to December 2023, neonatal screening data for HPA were retrospectively collected from the Yunnan Neonatal Screening Center. Neonates with presumptive positive screening results underwent confirmatory diagnosis through quantitative analysis of phenylalanine levels using tandem mass spectrometry. Subsequently, HPA-related genetic variants were identified by next-generation sequencing technology. Putative pathogenic mutations detected in probands were validated through Sanger sequencing of trios.

resultsA total of 1,261,043 newborn screening samples for phenylalanine were analyzed, with 125 cases confirmed as HPA. The overall incidence rates were 0.99 per 10,000 for HPA, 0.98 per 10,000 for PAHD, and 0.16 per 100,000 for tetrahydrobiopterin deficiency. Genetic analysis of hyperphenylalaninemia-related genes was performed in 84 children, revealing 49 PAH variants, 2 PTS variants, and 1 QDPR variant, with a total of 164 mutation sites identified. Missense mutations constituted the predominant variant type. The most frequent PAH mutations were c.728G > A/p.R243Q (26.88%), c.331C > T/p.R111* (9.38%), c.320A > G/p.H107R (8.13%), c.158G > A/p.A53H (7.50%), and c.441 + 2T > A/splicing (5.00%), with clustering observed in exons 7, 11, 6, and 3. A novel PAH mutation (c.60 + 4A > G/ p.?.) was identified.

conclusionsThe incidence and genetic mutation spectrum of HPA in Yunnan Province, Southwest China, exhibit distinctive characteristics when compared with other regions in China and international reports. These differences may be attributed to the unique geographical distribution of HPA patients and ethnic-specific genetic characteristics in this region. Furthermore, specific genetic mutations demonstrate potential associations with clinical phenotypes in PAHD. The novel PAH mutations identified in this study have expanded the current PAH gene database.