title: Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families.
abstract: We studied the molecular basis and genetic heterogeneity of hereditary antithrombin (III) deficiency in nine Dutch families. Polymerase chain reaction (PCR) amplification and direct sequencing of all antithrombin gene exons and flanking intronic regions identified mutations in eight families. Given the opportunity to correlate the molecular basis with survival, we addressed the relevance of molecular defects to mortality in inherited antithrombin deficiency. The defects included single nucleotide deletions (7671 del G, 7768-69 del G) and insertions (5501 ins A, 2463 G-->TC) that lead to frameshifts, a single base substitution [5381 C-->T (129Arg-->stop)] leading to a premature termination codon, and single base substitutions resulting in amino acid substitutions [2652 A-->C (63Tyr-->Ser), 13380 T-->C (421Ile-->Thr), and 13407 G-->T (430Cys-->Phe)]. All affected individuals were heterozygous for the defects. Previously we found in Dutch families that antithrombin deficiency did not lead to higher mortality compared with the general population. In accordance with these findings, we observed no excess mortality in the nine families [Observed:Expected, 52:52.6; standardised mortality ratio (SMR) 1.0, 95% confidence interval (CI), 0.7-1.3]. Our findings confirmed a considerable genetic heterogeneity underlying antithrombin deficiency. We therefore concluded that the lack of excess mortality in these families is not caused by a Dutch mild defect. We suggest that the longevity is not affected by molecular defects in the antithrombin gene and hypothesize that differences in mortality or natural history between families most likely result from other (genetic) risk factors.
authors.affiliation: Department of Clinical Epidemiology, University Hospital, Leiden, The Netherlands.
authors.forename: H H
authors.initials: HH
authors.lastname: van Boven
authors.forename: R J
authors.initials: RJ
authors.lastname: Olds
authors.forename: S L
authors.initials: SL
authors.lastname: Thein
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: D A
authors.initials: DA
authors.lastname: Lane
authors.forename: E
authors.initials: E
authors.lastname: Briët
authors.forename: J P
authors.initials: JP
authors.lastname: Vandenbroucke
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
mesh_terms: D000990:Antithrombin III / Q000235:genetics; D020152:Antithrombin III Deficiency; D001483:Base Sequence; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000401:mortality; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009426:Netherlands / Q000453:epidemiology; D017354:Point Mutation; D017384:Sequence Deletion; D013728:Terminator Regions, Genetic
chemical_list: D000990:Antithrombin III