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Maternal variants in NLRP and other maternal-effect proteins are associated with multi-locus imprinting disturbance in offspring

Maternal variants in NLRP and other maternal-effect proteins are associated with multi-locus imprinting disturbance in offspring
Maternal variants in NLRP and other maternal-effect proteins are associated with multi-locus imprinting disturbance in offspring
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 multi-locus imprinting disturbance.

Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multi-locus 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 multi-locus 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.
0022-2593
1-8
Begemann, Matthias
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Rezwan, Faisal I.
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Beygo, Jasmin
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Docherty, Louise E.
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Kolarova, Julia
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Schroeder, Christopher
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Buiting, Karin
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Chokkalingam, Kamal
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Degenhardt, Franziska
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Wakeling, Emma
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Kleinle, Stephanie
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Gonzalez Fassrainer, Daniela
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Oehl-Jaschkowitz, Barbara
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Turner, Claire L.S.
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Patalan, Michal
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Gizewska, Maria
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Binder, Gerhard
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Ngoc, Can Thi Bich
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Vũ, Dũng Chí
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Mehta, Sarju G.
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Baynam, Gareth S.
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Hamilton-Shield, Julian P.
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Aljareh, Sara
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Lokulo-Sodipe, Oluwakemi
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Horton, Rachel
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Siebert, Reiner
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Elbracht, Miriam
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Temple, I. Karen
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Eggermann, Thomas
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Mackay, Deborah J.G.
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Begemann, Matthias
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Rezwan, Faisal I.
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Beygo, Jasmin
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Docherty, Louise E.
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Kolarova, Julia
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Schroeder, Christopher
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Buiting, Karin
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Chokkalingam, Kamal
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Degenhardt, Franziska
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Wakeling, Emma
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Kleinle, Stephanie
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Gonzalez Fassrainer, Daniela
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Oehl-Jaschkowitz, Barbara
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Turner, Claire L.S.
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Patalan, Michal
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Gizewska, Maria
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Binder, Gerhard
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Ngoc, Can Thi Bich
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Vũ, Dũng Chí
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Mehta, Sarju G.
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Baynam, Gareth S.
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Hamilton-Shield, Julian P.
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Aljareh, Sara
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Lokulo-Sodipe, Oluwakemi
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Horton, Rachel
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Siebert, Reiner
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Elbracht, Miriam
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Temple, I. Karen
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Eggermann, Thomas
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Mackay, Deborah J.G.
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Begemann, Matthias, Rezwan, Faisal I., Beygo, Jasmin, Docherty, Louise E., Kolarova, Julia, Schroeder, Christopher, Buiting, Karin, Chokkalingam, Kamal, Degenhardt, Franziska, Wakeling, Emma, Kleinle, Stephanie, Gonzalez Fassrainer, Daniela, Oehl-Jaschkowitz, Barbara, Turner, Claire L.S., Patalan, Michal, Gizewska, Maria, Binder, Gerhard, Ngoc, Can Thi Bich, Vũ, Dũng Chí, Mehta, Sarju G., Baynam, Gareth S., Hamilton-Shield, Julian P., Aljareh, Sara, Lokulo-Sodipe, Oluwakemi, Horton, Rachel, Siebert, Reiner, Elbracht, Miriam, Temple, I. Karen, Eggermann, Thomas and Mackay, Deborah J.G. (2018) Maternal variants in NLRP and other maternal-effect proteins are associated with multi-locus imprinting disturbance in offspring. Journal of Medical Genetics, 1-8. (doi:10.1136/jmedgenet-2017-105190).

Record type: Article

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 multi-locus imprinting disturbance.

Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multi-locus 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 multi-locus 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.

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Accepted/In Press date: 15 February 2018
e-pub ahead of print date: 24 March 2018

Identifiers

Local EPrints ID: 418292
URI: https://eprints.soton.ac.uk/id/eprint/418292
ISSN: 0022-2593
PURE UUID: e906bcea-4165-4d83-8a25-e692732aa0c7
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for Oluwakemi Lokulo-Sodipe: ORCID iD orcid.org/0000-0002-8169-3384
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 27 Feb 2018 17:30
Last modified: 06 Jun 2018 12:54

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Contributors

Author: Matthias Begemann
Author: Faisal I. Rezwan ORCID iD
Author: Jasmin Beygo
Author: Louise E. Docherty
Author: Julia Kolarova
Author: Christopher Schroeder
Author: Karin Buiting
Author: Kamal Chokkalingam
Author: Franziska Degenhardt
Author: Emma Wakeling
Author: Stephanie Kleinle
Author: Daniela Gonzalez Fassrainer
Author: Barbara Oehl-Jaschkowitz
Author: Claire L.S. Turner
Author: Michal Patalan
Author: Maria Gizewska
Author: Gerhard Binder
Author: Can Thi Bich Ngoc
Author: Dũng Chí Vũ
Author: Sarju G. Mehta
Author: Gareth S. Baynam
Author: Julian P. Hamilton-Shield
Author: Sara Aljareh
Author: Oluwakemi Lokulo-Sodipe ORCID iD
Author: Rachel Horton
Author: Reiner Siebert
Author: Miriam Elbracht
Author: I. Karen Temple
Author: Thomas Eggermann

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