Prenatal diagnosis of Glanzmann thrombasthenia using the polymorphic markers BRCA1 and THRA1 on chromosome 17

Abstract

Glanzmann thrombasthenia is an autosomal recessive bleeding disorder caused by mutations in the genes encoding platelet GPIIb or GPIIIa. Both genes map to chromosome 17q21 and polymorphisms within this chromosomal region have been identified. In the current study, prenatal diagnosis was performed for a family that already had one affected child, patient 1, who had a compound heterozygous mutation in GPIIb. At the time of prenatal diagnosis, the maternal GPIIb mutation had been identified but the paternal GPIIb mutation was unknown. By sequence analysis, the fetus was identified as a carrier of the mother's mutation. To determine the probability of the fetus inheriting the father's mutation, haplotype analysis of DNA samples from the fetus, mother, father and affected child were performed using polymorphic markers on chromosome 17q12-q21. These markers included polymorphisms within the thyroid hormone receptor alpha1 gene (THRA1), the breast cancer gene (BRCA1), GPIIb, GPIIIa, and an anonymous marker D17S579. Heterozygosity within the THRA1, BRCA1 and GPIIIa polymorphic markers predicted that the fetus carried the father's normal allele. Based on genetic linkage studies, no recombination was identified with any of the informative markers, and from the map distance between GPIIb and BRCA1 the accuracy of diagnosis was predicted to be >98%. The father's mutation was subsequently identified and direct sequence analysis of fetal DNA confirmed that the fetus did not inherit the fathers' mutant allele.