The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening

ObjectivesThe purpose of this study was to identify the mutations responsible for phenylalanine hydroxylase deficiency in Cypriot patients detected through neonatal screening.Design and MethodsAnalysis of the PAH gene was performed by direct sequencing of the patients' genomic DNA, MLPA analysis and real-time PCR.ResultsAmong 22 independent alleles thirteen previously described mutations were detected (detection rate 100%), all in compound heterozygosity: p.Arg395Gly (18.2%), c.168 + 5 G > C (13.6%), p.EX3del (9%), c.1066-11 G > A (9%), p.Ala403Val (9%), p.Glu178Gly (9%), p.Ser70Pro (4.5%), p.Arg241His (4.5%), p.Phe55fs (4.5%), p.Arg158Gln (4.5%), p.Asp222Gly (4.5%), p.Ala300Ser (4.5%), p.Pro225Thr (4.5%). Of the ten different genotypes, three have been previously reported to be associated with a mild clinical phenotype and to respond to tetrahydrobiopterin (BH4) administration.ConclusionsMarked genetic heterogeneity was found in Cypriot patients with hyperphenylalaninemia with two mutations accounting for 32% of the alleles. Most of the mutations detected have been found in other European and Mediterranean populations.

► Results of Cypriot PKU neonatal screening programme.
► PHA mutations in Cypriot patients with hyperphenylalaninemia.
► Direct sequencing and MLPA analysis identified 13 previously known mutations.
► Two most common mutations are p.Arg395Gly (18.2%) and c.168 + 5 G > C (13.6%).
► Ten different genotypes all compound heterozygous, three predicted to respond to BH4.