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An effect of fetal genotype on PE risk is demonstrated by the high risk associated with some human trisomies and mutations in rare cases of familial PE. PE is associated with trisomy 13 and 16 but not trisomy 18 or 21.^113–116 In fact, a reduction in the risk of PE was observed in a large study of trisomy 21 (relative risk of 0.19).¹¹⁵ One in four pregnancies surviving past 20 weeks with trisomy 16 confined to the placental tissues is associated with PE (mostly EOPE).^{69, 70} The varying risk for PE with different trisomies likely reflects distinct effects on placental development. In trisomy 21, both placenta and fetus are normally sized and show normal⁷⁸ blood flow by Doppler ultrasound.^117–119 However, trisomy 21 has a deficiency in formation of the syncytiotrophoblast,^{117, 118} which could lower the risk of PE because of a reduction in syncytiotrophoblast apoptosis.

Genetic linkage in large pedigrees segregating for PE has identified mutations in ACVR2A^{120, 121} and STOX1.^{122, 123} These mutations appear though to be rare and found in only isolated pedigrees. BWS due to mutations in CDKN1C has also been linked with increased risk for PE.¹²⁴ In addition, there is some evidence for contribution of genetic variants in several genes, including HLA genotypes and variants in FLT1, to risk of PE.^{125, 126}