Large heterozygous deletion masquerading as homozygous missense mutation: A pitfall in diagnostic mutation analysis

The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. Thi s can be problematic when only part of the gene is examined or when relevan t DNA alterations are not recognized by standard methods. We present a chil d in whom phenylketonuria was apparently caused by homozygosity for the mut ation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However , the clinical severity of the disease was not quite as mild as expected, t he mutation was not identified in the father despite confirmed paternity, a nd the paternal allele showed a highly unusual pattern of polymorphic marke rs in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. D iagnostic DNA analyses should include a comprehensive examination of the wh ole relevant gene in the patient and confirmation of carrier status in both parents.