NLRP genes and their role in preeclampsia and multi-locus imprinting disorders.

Preeclampsia (PE) affects 2-5% of all pregnancies. It is a multifactorial disease, but it has been estimated that 35% of the variance in liability of PE are attributable to maternal genetic effects and 20% to fetal genetic effects. PE has also been reported in women delivering children with Beckwith-Wiedemann syndrome (BWS, OMIM 130650), a disorder associated with aberrant methylation at genomically imprinted loci. Among others, members of the NLRP gene family are involved in the etiology of imprinting defects. Thus, a functional link between PE, NLRP gene mutations and aberrant imprinting can be assumed. Therefore we analyzed a cohort of 47 PE patients for NLRP gene mutations by next generation sequencing. In 25 fetuses where DNA was available we determined the methylation status at the imprinted locus. With the exception of one woman heterozygous for a missense variant in the NLRP7 gene (NM_001127255.1(NLRP7):c.542G>C) we could not identify further carriers, in the fetal DNA normal methylation patterns were observed. Thus, our negative screening results in a well-defined cohort indicate that NLRP mutations are not a relevant cause of PE, though strong evidence for a functional link between NLRP mutations, PE and aberrant methylation exist.