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 activit y as well as low plasma AT antigen were documented in the propositus, but n ot in the parents, or in a male sibling. AT gene analysis by sequencing pol ymerase chain reaction-amplified genomic DNA from exon 5 of the propositus revealed a novel point mutation, GAG-->TAG at codon 271, resulting in a sto p codon (Glu271STOP). This mutation was not demonstrable in the other membe rs of his immediate family. DNA marker polymorphism analysis indicated the expected parentage. Based on allele frequency data for Caucasians in the Un ited 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 th e various family members, which also confirmed maternity and paternity. The se studies provide documentation of the first spontaneous mutation of an AT gene in a thrombophilic individual, resulting in a type I AT deficiency. ( C) 1999 Wiley-Liss, Inc.