A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.
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.
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zürich, Switzerland.
Corinne
C
Gemperle-Britschgi
Center of Newborn Screening, Department of Pediatrics, Institute for Mother and Child Care, Bucharest, 120 Lacul Tei Blv., 020395, Romania.
Daniela
D
Iorgulescu
"I. Hatieganu" University of Medicine and Pharmacy - Cluj-Napoca, Department of Neurology, Romania.
Monica Alina
MA
Mager
"Gr.T.Popa" University of Medicine and Pharmacy, Newborn Screening Center Iasi, 3rd Clinic of Pediatrics, Romania.
Dana
D
Anton-Paduraru
"I.Hatieganu" University of Medicine and Pharmacy - Cluj-Napoca, Department of Molecular Sciences, Cluj-Napoca, Romania; Cognitive Neuroscience Laboratory, Babes-Bolyai University - Cluj-Napoca, Romania. Electronic address: vulturar.romana@umfcluj.ro.
Romana
R
Vulturar
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zürich, Switzerland; Division of Metabolism, Department of Pediatrics, University of Zurich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland; Neuroscience Centre Zürich, University of Zürich, Zürich, Switzerland; Neuroscience Centre Zürich, ETH Zürich (ZNZ), Zürich, Switzerland; Children's Research Centre (CRC), Zürich, Switzerland. Electronic address: beat.thony@kispi.uzh.ch.
Beat
B
Thöny
D002461:Cell Line, Transformed; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000378:metabolism; D010661:Phenylketonurias / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D012383:Romania / Q000453:epidemiology; D017384:Sequence Deletion
D010651:Phenylalanine Hydroxylase
Hyperphenylalaninemia; Mutation analysis; Phenylketonuria