A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population

Gene. 2016 Jan 15;576(1 Pt 1):182-8. doi: 10.1016/j.gene.2015.10.020. Epub 2015 Oct 21.


The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.

Keywords: Hyperphenylalaninemia; Mutation analysis; Phenylketonuria.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Female
  • Humans
  • Male
  • Mutation, Missense*
  • Phenylalanine Hydroxylase / genetics*
  • Phenylalanine Hydroxylase / metabolism
  • Phenylketonurias / enzymology
  • Phenylketonurias / epidemiology
  • Phenylketonurias / genetics*
  • Romania / epidemiology
  • Sequence Deletion*


  • Phenylalanine Hydroxylase