A novel and de novo spontaneous point mutation (Glu271STOP) of the antithrombin gene results in a type I deficiency and thrombophilia.

We describe a novel, de novo point mutation in one antithrombin (AT) allele resulting in type I AT deficiency and thrombophilia. Low plasma AT activity as well as low plasma AT antigen were documented in the propositus, but not in the parents, or in a male sibling. AT gene analysis by sequencing polymerase chain reaction-amplified genomic DNA from exon 5 of the propositus revealed a novel point mutation, GAG-->TAG at codon 271, resulting in a stop codon (Glu271STOP). This mutation was not demonstrable in the other members of his immediate family. DNA marker polymorphism analysis indicated the expected parentage. Based on allele frequency data for Caucasians in the United States the cumulative paternity index, or CPI, for the propositus and his father is 219,077. This corresponds to a probability of paternity of 99.9995% based on a prior probability of 50%. Included in this analysis is a linkage analysis of a trinucleotide repeat in intron 5 of the AT gene of the various family members, which also confirmed maternity and paternity. These studies provide documentation of the first spontaneous mutation of an AT gene in a thrombophilic individual, resulting in a type I AT deficiency.