ENOrphanet Journal of Rare Diseases | Genetic Mutations and Phenotypic Features of Hyperphenylalaninemia in Yunnan Province
Date: April 05, 2025
Classification: Frontiers
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This study systematically reveals the mutation spectrum and phenotypic distribution of Hyperphenylalaninemia (HPA) in Yunnan children, Southwest China, identifying high-frequency mutation sites such as c.728G>A/p.R243Q and c.331C>T/p.R111*, and identifying a novel PAH gene splice site mutation. It provides important references for genetic basis research and clinical management of HPA in this region.
Literature Overview
This paper, The incidence rate and gene mutation characteristics of hyperphenylalaninemia in Yunnan Province, Southwest China, published in the Orphanet Journal of Rare Diseases, reviews and summarizes the newborn screening data for Hyperphenylalaninemia (HPA) collected at the Yunnan Neonatal Screening Center from 2013 to 2023. Genetic mutation analysis was conducted using next-generation sequencing and Sanger sequencing on confirmed cases, providing the first report of the PAH mutation spectrum and its phenotypic correlation in Southwest China. A total of 1,261,043 screening samples were analyzed, identifying 125 HPA cases, of which 84 underwent genetic testing, revealing 49 PAH mutations, 2 PTS mutations, and 1 QDPR mutation. The study found that PAH mutations were mainly concentrated in exons 7, 11, 6, and 3, and identified a novel splice site mutation c.60+4A>G/p.?, previously unreported in existing databases.
Background Knowledge
Hyperphenylalaninemia (HPA) is an autosomal recessive disorder mainly caused by deficiencies in phenylalanine hydroxylase (PAH) and its cofactor tetrahydrobiopterin (BH4). Mutations in the PAH gene lead to impaired phenylalanine metabolism, resulting in classical phenylketonuria (cPKU) or mild phenotypes (mPKU/mHPA). The global average incidence of PAH deficiency (PAHD) is approximately 0.64/10,000, but significant variation exists across different regions and ethnicities. In China, the overall incidence of PAHD is about 0.68/10,000, with p.A243G being the predominant mutation in the North and p.R243Q in the South. However, due to its multi-ethnic population and geographical isolation, Yunnan may exhibit a distinct mutation profile. BH4 deficiency (BH4D) can lead to neurotransmitter synthesis disorders and must be differentiated from PAHD. This study aims to fill the gap in genotype-phenotype correlations of PAHD in Southwest China and provide data support for clinical follow-up, genetic counseling, and prenatal diagnosis.
Study Methods and Experiments
The research team retrospectively collected neonatal phenylalanine screening data from Yunnan from 2013 to 2023. Screening was conducted using time-resolved fluorescence immunoassay, and diagnosis was confirmed using tandem mass spectrometry (MS/MS). Genetic mutation detection was performed using target exon sequencing of HPA-related genes (including PAH, PTS, QDPR, GCH1), with an average sequencing depth ≥100×. Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect large deletions or duplications in the PAH gene. Whole-genome sequencing was further applied to samples without identified mutations to rule out non-coding or complex structural variants. Mutation pathogenicity was assessed in accordance with ACMG guidelines, integrating bioinformatics tools (e.g., SIFT, Polyphen2, CADD) and disease databases (ClinVar, HGMD).
Key Findings and Insights
Significance and Future Directions
This study provides the first systematic report on the mutation spectrum of PAHD in Yunnan, Southwest China, revealing distinct mutation frequency distributions compared with Han Chinese and other regions, thus offering critical data for regional genetic counseling and prenatal diagnosis. The newly identified splice mutation enriches the PAH mutation database and provides new clues for future studies on pathogenic mechanisms. Additionally, the findings suggest the presence of unique PAH mutation hotspots among different ethnic groups, warranting further investigation with larger sample sizes and functional validation.
Conclusion
By analyzing neonatal screening and genetic mutations over the past decade in Yunnan, this study reveals the incidence, mutation spectrum, and phenotypic correlations of PAHD in the region. It identifies significant differences in mutation types and distributions compared with other regions in China. Notably, c.728G>A/p.R243Q remains the major mutation, but c.320A>G/p.H107R and c.441+2T>A are found at high frequency only in Yunnan, especially among ethnic minorities. The newly identified splice mutation c.60+4A>G/p.? was reclassified as pathogenic after comprehensive analysis. These findings expand the existing PAH mutation database and provide scientific evidence for clinical management, genetic counseling, and prenatal diagnosis of PAHD in this region. Future studies may incorporate functional assays and larger cohorts to further validate the pathogenic mechanisms and their phenotypic impacts, advancing precision medicine in rare disease research.
