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. 2018 Jul;55(7):497-504.
doi: 10.1136/jmedgenet-2017-105190. Epub 2018 Mar 24.

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Matthias Begemann  1 , Faisal I Rezwan  2 , Jasmin Beygo  3 , Louise E Docherty  4 , Julia Kolarova  5 , Christopher Schroeder  3 , Karin Buiting  3 , Kamal Chokkalingam  6 , Franziska Degenhardt  7 , Emma L Wakeling  8 , Stephanie Kleinle  9 , Daniela González Fassrainer  9 , Barbara Oehl-Jaschkowitz  10 , Claire L S Turner  11 , Michal Patalan  12 , Maria Gizewska  12 , Gerhard Binder  13 , Can Thi Bich Ngoc  14 , Vu Chi Dung  14 , Sarju G Mehta  15 , Gareth Baynam  16   17 , Julian P Hamilton-Shield  18 , Sara Aljareh  2 , Oluwakemi Lokulo-Sodipe  2   19 , Rachel Horton  2   19 , Reiner Siebert  5 , Miriam Elbracht  1 , Isabel Karen Temple  2   19 , Thomas Eggermann  1 , Deborah J G Mackay  2
Affiliations

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Matthias Begemann et al. J Med Genet. 2018 Jul.

Abstract

Background: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.

Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.

Results: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.

Conclusion: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Keywords: Beckwith-Wiedemann syndrome; NLRP2; NLRP5; NLRP7; PADI6; Silver-Russell syndrome; genomic imprinting; multi-locus imprinting disorder.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Pedigrees of selected families affected by multilocus imprinting disorders. (A) Family 1 with two BWS-MLID children, who were additionally reported to be developmentally delayed. (B) Family 6 with recurrent pregnancy loss and stillbirths, and one child with MLID and features reminiscent of BWS. BWS, Beckwith-Wiedemann syndrome; gw, gestational weeks; MLID, multilocus imprinting disturbance.
See this image and copyright information in PMC

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