Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Shanxi province

Brain Dev. 2021 Feb;43(2):220-229. doi: 10.1016/j.braindev.2020.08.012. Epub 2020 Sep 4.


Background: Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive inborn error that affects phenylalanine (Phe) metabolism. It has a complex phenotype with many variants and genotypes among different populations. Shanxi province is a high-prevalence area of PAHD in China.

Methods: In this study, eighty-nine PAHD patients were subjected to genetic testing using Sanger sequencing, followed by multiplex ligation-dependent probe amplification analysis (MLPA). Allelic and genotypic phenotype values (APV and GPV, respectively) were used for genotype-based phenotypic prediction.

Results: Fifty-one types of variants, including three novel forms, were identified. The predominant variant was p.R243Q (22.09%), followed by p.R53H (10.47%), p.EX6-96A > G (9.30%), p.V399V (5.23%) and p.R413P (3.49%). Notably, mild hyperphenylalaninemia (MHP) has a high prevalence in this region (up to 45.76%), and the variant p.R53H was solely observed in patients of MHP. According to the genotype-phenotype prediction, the APV/GPV system was well correlated with the metabolic phenotype of most PAHD patients.

Conclusion: We have systematically constructed the mutational and phenotypic spectrum of PAH in Shanxi province. Hence, this study will help to further understand the genotype-phenotype associations in PAHD patients, and it may offer more reliable genetic counseling and management.

Keywords: Allelic phenotype value; Genotype-Phenotype correlation; Genotypic phenotype value; Hyperphenylalaninemia; Mutational spectrum.

MeSH terms

  • Alleles
  • Asian People / genetics
  • China / epidemiology
  • Female
  • Gene Frequency / genetics
  • Genetic Association Studies / methods
  • Genotype
  • Humans
  • Infant, Newborn
  • Male
  • Neonatal Screening / methods
  • Phenotype
  • Phenylalanine Hydroxylase / genetics*
  • Phenylalanine Hydroxylase / metabolism
  • Phenylketonurias / genetics*
  • Phenylketonurias / metabolism


  • Phenylalanine Hydroxylase