Modulation of phenotypic expression of APOA5 Q97X and L242P mutations.

OBJECTIVE: To provide phenotypic and functional data in new patients with APOA5 mutations and to identify genetic and metabolic factors influencing their phenotypic expression. METHODS AND RESULTS: By sequencing APOA5 gene in a cohort of 286 hyperchylomicronemic subjects, free of LPL or APOC2 mutations, we identified 4 unrelated carriers of the Q97X mutation (3 heterozygotes and 1 homozygote) and one heterozygote with a new L242P mutation. Postheparin LPL activity level was reduced by about 50% in Q97X heterozygotes and more than 90% in the Q97X homozygote, but was normal in the L242P patient after resolution of hyperchylomicronemia. Plasma apoAV was undetectable in the Q97X homozygote and in the normal range in the L242P and Q97X heterozygous carriers. In Western blot studies, the association of apoAV with plasma lipoproteins was altered in Q97X heterozygous carriers but not in the L242P carrier. Hyperchylomicronemic heterozygotes for both mutations carried an additional APOA5 variant haplotype and/or APOE variant (E2 or E4). Type 2 diabetes or metabolic syndrome were not a major phenotypic determinant. CONCLUSIONS: The L242P mutation was present in a hyperchylomicronemic proband but its causal involvement remains to be established. The Q97X mutation was clearly involved in hyperchylomicronemia with evidence of concomitant altered intravascular lipolysis, and a complete apoAV deficiency in the homozygote. The phenotypic expression variability of APOA5 mutations was mostly influenced by compound heterozygosity with APOA5 variant haplotypes plus additional genetic factors, and in a lesser extent by the metabolic environment.

False-positive results in neonatal screening for cystic fibrosis based on a three-stage protocol (IRT/DNA/IRT): Should we adjust IRT cut-off to ethnic origin?

Since 1979, newborn screening for cystic fibrosis (CF) has been possible by measuring immunoreactive tryspinogen (IRT) in blood spots. In France, a programme based on a three-stage strategy (IRT/DNA/IRT) started in 2002. In the Rhône-Alpes area, the positive screening rate (i.e. the proportion of samples sent for genotyping) observed after the first IRT measurement was higher than the expected rate (0.65% versus 0.50%), without a greater CF incidence. We hypothesized that the IRT reference range could differ according to the ethnic origin of the newborns. 35 141 newborns were studied and divided into two groups: European ethnic group 26 324 (75%) and North African ethnic group 8817 (25%). 243 positive newborns were identified: 146 (60%) in the European ethnic group and 97 (40%) in the North African ethnic group. Three CF patients and 11 unaffected heterozygotes were found in the European group, but no mutations were found in the North African group. Mean IRT values and the percentage of IRT values over the cut-off were significantly higher in the North African group than in the European group (mean IRT = 21.17 microg/L and 19.74 microg/L, p < 0.0001; %IRT > cut-off = 1.1% and 0.5%, respectively). For the positive screened newborns, term and IRT mean were comparable, whereas birth weight was higher in the North African ethnic group. These results lead us to conclude that (i) newborns from families of North African origin have higher IRT values and (ii) most of the positive screened newborns in this population could be considered as 'false positives'. These conclusions could explain, in part, the large variations seen in the positive screening rate in the French CF neonatal screening and raise the question whether it is relevant to adapt cut-off to ethnic origin of the newborns.