Non-invasive first-trimester detection of paternal beta-globin gene mutations and polymorphisms as predictors of thalassemia risk at chorionic villous sampling.

OBJECTIVE The objective was to evaluate the beta-globin gene mutations and polymorphisms in cell-free fetal DNA in the early first trimester (7-9th weeks' gestation) for the prediction of thalassemia risk at chorionic villous sampling (CVS). STUDY DESIGN Beta-globin gene mutations and polymorphisms were analyzed in 97 carrier families and 100 control couples. Using conventional PCR-DGGE we carried out cell-free fetal DNA analysis in 37 couples in whom only the father was an IVSI-110 carrier. RESULTS Beta-globin gene mutations have 80% information content in contrast to 39% of polymorphisms. By non-invasive early first-trimester identification of the paternally transmitted IVSI-110 mutation, we reached a sensitivity and specificity of 96 and 100%, respectively. Although the detection rate of the Y chromosome in male fetuses was as high as 100%, beta-thalassemia allele drop-out cannot be excluded. CONCLUSIONS Even though there is high sensitivity in non-invasive paternally transmitted beta-thalassemia mutation detection, intense effort must be made to avoid misdiagnoses before the clinical application of this approach.