title: Mutations at the galactose-1-p-uridyltransferase gene in infants with a positive galactosemia newborn screening test.
abstract: Newborn screening for galactosemia yields a high number of false-positive results. Confirmatory DNA testing for unknown galactosemia mutations on the initial positive sample using novel techniques of mutation detection tenders itself to reduce the recall rate. The potential benefits of confirmatory DNA testing, however, could be offset by the detection of a high percentage of galactosemia carriers, Duarte/galactosemia compound heterozygotes, and infants with benign sequence changes in the galactose-1-phosphate uridyltransferase (GALT) gene among infants with a positive biochemical screening test. Our aim was to determine the frequency and allelic distribution of all sequence changes in the GALT gene in 110 newborns with a positive total galactose screening test among 43,688 Austrian newborns screened consecutively. We found that only 20 of the 110 probands carried at least one known or novel candidate galactosemia mutation (one galactosemia homozygote, 7 Duarte/galactosemia compounds, 12 carriers) as judged by denaturing gradient gel electrophoresis and cleavage fragment length polymorphism analysis. Four novel galactosemia candidate mutations (Q9H, A46fsdelCAGCT, M129T, L342I) were identified. Sixty-seven probands had no detectable sequence changes and 23 carried only the benign Duarte or Los Angeles variant alleles or silent mutations. We conclude that a rapid and automatable confirmation test for unknown GALT mutations, e.g. on a high-density oligonucleotide array basis, has the potential to lower the recall rate of galactosemia screening in our population by about five-fold from 0.25 to 0.046%. Further research, however, will be required before the development of such a test can be advocated.
authors.affiliation: Department of Pediatrics, University of Vienna, Austria.
authors.forename: Chike
authors.initials: C
authors.lastname: Item
authors.forename: Brian P
authors.initials: BP
authors.lastname: Hagerty
authors.forename: Adolf
authors.initials: A
authors.lastname: Mühl
authors.forename: Susanne
authors.initials: S
authors.lastname: Greber-Platzer
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stöckler-Ipsiroglu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Strobl
mesh_terms: D001317:Austria; D005189:False Positive Reactions; D005693:Galactosemias / Q000175:diagnosis* / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D015997:Neonatal Screening; D011110:Polymorphism, Genetic; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics*
chemical_list: D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase