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. 2017 Aug;25(8):924-929.
doi: 10.1038/ejhg.2017.94. Epub 2017 May 31.

Maternal Heterozygous NLRP7 Variant Results in Recurrent Reproductive Failure and Imprinting Disturbances in the Offspring

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Free PMC article

Maternal Heterozygous NLRP7 Variant Results in Recurrent Reproductive Failure and Imprinting Disturbances in the Offspring

Lukas Soellner et al. Eur J Hum Genet. .
Free PMC article

Abstract

It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternal heterozygous NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-year-old woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Next-generation sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p.(Phe671Glnfs*18)). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Family pedigree. (* these family members were sequenced for the variant c.2010_2011del, p.(Phe671Glnfs*18)).
Figure 2
Figure 2
Examples of copy number (upper tracks) and methylation profiles (lower tracks) from MS-MLPA of DNA of fetus IV.1 (a1 and a2) and fetus IV.3 (b). Each probe is represented by a dot and targets either an imprinted, a non-imprinted or a control sequence. Normal copy number results (upper tracks) are shown as black dots, hypomethylation is represented by purple/red dots, hypermethylation by blue dots. The arbitrary ratio border (red and blue line) indicates a 20% signal increase/loss. (a) MS-MLPA with a chromosome 11 specific kit (ME030, MRC Holland) in DNA from blood of fetus IV.1 shows a mild KCNQ1OT1 hypomethylation (a1) and a complete loss of methylation for GRB10 and MEST (red dots) on chromosome 7 (kit ME032) in DNA from tendon (a2). (b) For fetus IV.3, aberrant methylation was detected for chromosome 20 imprinted loci (kit ME031). Copy number analyses did not show any abnormalities.
Figure 3
Figure 3
Identification of the 2 bp deletion in exon 5 of the NLRP7 gene by clinical exome next-generation sequencing (c.2010_2011del, p.(Phe671Glnfs*18)) with a total coverage of 183 reads. The minimum coverage threshold was set to 30 reads (indicated by dashed red lines).The number of forward and reverse reads is represented by light and dark blue bars, respectively.

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