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Deep Intronic PAH Variants Explain Missing Heritability in Hyperphenylalaninemia.

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Deep intronic variants in the phenylalanine hydroxylase (PAH) gene significantly improve the diagnostic rate for phenylketonuria (PKU) and hyperphenylalaninemia (HPA). These variants, often causing pseudoexon inclusion, help solve previously genetically unexplained cases.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Biochemistry

Background:

  • Phenylalanine hydroxylase (PAH) deficiency, or phenylketonuria (PKU), is a common genetic disorder causing hyperphenylalaninemia (HPA).
  • Approximately 5% of HPA cases remain genetically unsolved, limiting accurate diagnosis and genetic counseling.
  • Identifying novel genetic variants, particularly deep intronic ones, is crucial for improving diagnostic yield.

Purpose of the Study:

  • To investigate the role of deep intronic variants in the PAH gene in genetically unsolved HPA patients.
  • To determine the impact of these variants on pre-mRNA splicing and protein function.
  • To enhance the molecular diagnostic rate for HPA.

Main Methods:

  • Next-generation sequencing (NGS) was used to analyze the entire PAH gene in 96 unsolved HPA patients.
  • Minigene-based splicing assays were employed to assess the functional effects of identified deep intronic variants.
  • Allelic phenotype values were calculated for recurrent deep intronic variants.

Main Results:

  • Twelve deep intronic PAH variants were identified in 80.2% of patients, with ten being novel.
  • These variants, located in introns 5, 6, 10, and 11, caused pseudoexon inclusion, leading to frameshift or elongated proteins.
  • The most frequent variants were c.1199+502A>T, c.1065+241C>A, c.1065+258C>A, and c.706+531T>C, with assigned phenotypes ranging from classic PKU to mild HPA.
  • The diagnostic rate for HPA increased from 95.3% to 99.3% after identifying these deep intronic variants.

Conclusions:

  • Deep intronic PAH variants significantly improve the diagnostic rate for HPA, highlighting the importance of analyzing non-coding regions.
  • Pseudoexon inclusion is a recurrent mechanism by which deep intronic variants disrupt PAH gene function.
  • These findings underscore the necessity of comprehensive genetic analysis, including deep intronic variants, for diagnosing genetic disorders.