ENOrphanet Journal of Rare Diseases | Genetic Mutation Profile and Phenotypic Analysis of Hyperphenylalaninemia in Yunnan Province
Date: April 05, 2025
Classification: Frontiers
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This study reviews the neonatal screening data of hyperphenylalaninemia in Yunnan Province, China, from 2013 to 2023. It systematically analyzed the PAH gene mutation spectrum and, for the first time, reported the genotype-phenotype correlation features of PAHD patients in Southwest China. A novel PAH splice site mutation was also identified, providing critical reference for genetic counseling, prenatal diagnosis, and personalized treatment of the disease.
Literature Summary
The article titled 'The incidence rate and gene mutation characteristics of hyperphenylalaninemia in Yunnan Province, Southwest China' was published in the Orphanet Journal of Rare Diseases. It reviews and summarizes the neonatal screening data of hyperphenylalaninemia (HPA) in Yunnan Province over the past decade, systematically analyzing the types and phenotypic distribution of PAH gene mutations. This study also reports, for the first time in children from Southwest China, the PAH mutation profile and identifies a new splice site mutation, offering foundational evidence for optimizing clinical follow-up, genetic counseling, and prenatal molecular diagnosis.Background Information
Hyperphenylalaninemia (HPA) is an autosomal recessive metabolic disorder primarily caused by phenylalanine hydroxylase (PAH) deficiency or impaired metabolism of its cofactor, tetrahydrobiopterin (BH4), leading to abnormally elevated levels of phenylalanine in the blood. Among these, PAH deficiency (PAHD) is the most common form, with clinical phenotypes ranging from mild HPA requiring no treatment to classic phenylketonuria (cPKU), which requires strict low-phenylalanine dietary intervention. BH4 deficiency (BH4D) not only increases phenylalanine levels but may also reduce neurotransmitters such as dopamine and serotonin, potentially leading to severe neurological symptoms. The incidence rate of HPA varies significantly across different global regions and ethnicities. The average PAHD incidence in China is approximately 0.68/10,000. Yunnan Province, a multi-ethnic region, shows a distinct mutation profile compared to other regions in China, suggesting a unique genetic background. This study aims to fill the gap in genotype-phenotype correlation research for PAHD in Southwest China and provide scientific basis for genetic counseling, prenatal diagnosis, and neonatal intervention strategies.
Research Methods and Experiments
From January 2013 to December 2023, researchers collected neonatal screening data for hyperphenylalaninemia from the Yunnan Neonatal Screening Center, analyzing a total of 1,261,043 samples. Positive screening results were confirmed using tandem mass spectrometry (MS/MS) for quantitative phenylalanine concentration measurement. Whole-exome sequencing and MLPA analysis were then performed on diagnosed children to identify mutation sites in the PAH and related genes (e.g., PTS, QDPR). Sanger sequencing was used to verify mutations within the families. The pathogenicity of all mutation sites was assessed according to the ACMG guidelines, incorporating bioinformatics prediction, disease database searches, and literature references.Key Findings and Insights
Research Implications and Future Directions
This study is the first systematic report of the PAH gene mutation profile in Southwest China, providing critical data for clinical subtyping, genetic counseling, and prenatal diagnosis of hyperphenylalaninemia. The newly identified splice site mutation enriches the PAH mutation database, facilitating more accurate molecular diagnosis. Future research should expand the sample size and incorporate enzyme activity testing to further explore the gene-dosage effects between genotype and phenotype. Moreover, the findings suggest that ethnic-specific mutation frequencies should be considered in genetic screening in multi-ethnic regions to improve screening strategies.
Conclusion
This study, based on neonatal screening data from the past decade in Yunnan Province, systematically analyzed the incidence rate of hyperphenylalaninemia, the mutation profile of the PAH gene, and its correlations with clinical phenotypes. The findings revealed a higher PAHD incidence in Yunnan compared to the national average, with distinct regional and ethnic mutation characteristics. The newly identified splice site mutation (c.60+4A>G) provides a novel reference for genetic diagnosis in this region. Furthermore, the study supports the gene-dosage effect hypothesis of PAH genotypes and phenotypes, offering a genetic basis for clinical subtyping and treatment decisions. These results not only help optimize the screening and diagnostic procedures for hyperphenylalaninemia in Yunnan but also provide regional reference data for genetic disease studies across different ethnic groups in China. In the future, with more functional studies, the pathogenic mechanisms of these mutation sites will become clearer, promoting the development of precision medicine and genetic counseling.
