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Hereditary antithrombin deficiency: heterogeneity of the molecular basis
and mortality in Dutch families
HH van Boven, RJ Olds, SL Thein, PH Reitsma, DA Lane, E Briet, JP Vandenbroucke and FR Rosendaal
Department of Clinical Epidemiology, University Hospital, Leiden, The
Netherlands.
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.
Volume 84,
Issue 12,
pp. 4209-4213,
12/15/1994
Copyright © 1994 by The American Society of Hematology
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