PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype–phenotype associations
✍ Scribed by Min Ki ten Kate; Mathieu Platteel; Rene Mulder; Peter Terpstra; Gerry A.F. Nicolaes; Pieter H. Reitsma; Gerrit van der Steege; Jan van der Meer
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 356 KB
- Volume
- 29
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
Communicated by Ju ¨rgen Horst
Hereditary protein S (PS) deficiency predisposes to venous thrombosis. Previously, we demonstrated a difference in risk of venous thrombosis between PS deficiency type I and type III. We used direct sequencing, multiplex ligation-dependent probe amplification (MLPA), and linkage analysis to study whether this difference could be explained by molecular heterogeneity. The study contained two sets of families with PS deficiency type I (cohort 1; 35 probands, 155 relatives) or type III (cohort 2; 52 probands, 241 relatives). In cohort 1, a mixed type I/type III PS-deficient phenotype was observed in 66% of the pedigrees. A total of 34 probands carried a mutant PROS1 allele, compared to one proband in cohort 2 (Po10 À10 ). The proband's mutation was identified in all type I, but only in 57% of type III PS deficient relatives. MLPA-analysis in the mutation negative families did not reveal PROS1 deletions or insertions. Linkage analysis in 16 families showed cosegregation of PROS1 markers in the family with type I deficiency, but not in the 15 families with type III deficiency. The genotype-phenotype associations point to differences in genetic architecture. Whereas PS deficiency type I is a monogenic disease due to PROS1 allelic heterozygosity, PS deficiency type III is most likely a more complex or heterogeneous disorder.