The term multilocus imprinting disturbance (MLID) describes the aberrant methylation of multiple imprinted loci in the genome, and MLID occurs in patients suffering from imprinting disorder carrying methylation defects. First data indicate that functional variants in factors expressed from both the fetal as well as the maternal genome cause MLID. Molecular changes in such genes of the maternal genome are called maternal effect variants, they affect members of the subcortical maternal complex (SCMC) in the oocyte which plays an important role during early embryonic development. Whereas the contribution of variants in the SCMC genes NLRP2, NLRP5, NLRP7, and KHDC3L to the etiology of reproductive failure and aberrant imprinting is widely accepted, the involvement of PADI6 variants in the formation of MLID is in discussion. We now report on the identification of biallelic variants in a woman suffering from different miscarriages and giving birth to two children with MLID. Thereby the role of PADI6 in maintaining the proper imprinting status during early development is confirmed. Thus, PADI6 variants do not only cause (early) pregnancy losses, but maternal effect variants in this gene cause the same spectrum of pregnancy outcomes as variants in other SCMC encoding genes, including chromosomal aberrations and disturbed imprinting. The identification of maternal effect variants requires genetic and reproductive counseling as carriers of these variants are at high risks for reproductive failure.
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Sanchez-Delgado M, Riccio A, Eggermann T, Maher ER, Lapunzina P, Mackay D, et al. Causes and consequences of multi-locus imprinting disturbances in humans. Trends Genet. 2016;32:444–55.
Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008;40:949–51.
Azzi S, Rossignol S, Steunou V, Sas T, Thibaud N, Danton F, et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet. 2009;18:4724–33.
Begemann M, Rezwan FI, Beygo J, Docherty LE, Kolarova J, Schroeder C, et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. J Med Genet. 2018;55:497–504.
Monk D, Sanchez-Delgado M, Fisher R. NLRPs, the subcortical maternal complex and genomic imprinting. Reproduction. 2017;154:R161–R70.
Soellner L, Begemann M, Degenhardt F, Geipel A, Eggermann T, Mangold E. Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring. Eur J Hum Genet. 2017;25:924–9.
Docherty LE, Rezwan FI, Poole RL, Turner CL, Kivuva E, Maher ER, et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat Commun. 2015;6:8086.
Sparago A, Verma A, Patricelli MG, Pignata L, Russo S, Calzari L, et al. The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype. Clin Epigenetics. 2019;11:190.
Xu Y, Shi Y, Fu J, Yu M, Feng R, Sang Q, et al. Mutations in PADI6 cause female infertility characterized by early embryonic arrest. Am J Hum Genet. 2016;99:744–52.
Wang X, Song D, Mykytenko D, Kuang Y, Lv Q, Li B, et al. Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest. Reprod Biomed Online. 2018;36:698–704.
Robbins SM, Thimm MA, Valle D, Jelin AC. Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes. J Assist Reprod Genet. 2019;36:1539–48.
Zheng W, Chen L, Dai J, Dai C, Guo J, Lu C, et al. New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage. J Assist Reprod Genet. 2020;37:205–12.
Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet. 2018;26:1007–13.
Yurttas P, Vitale AM, Fitzhenry RJ, Cohen-Gould L, Wu W, Gossen JA, et al. Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Development. 2008;135:2627–36.
Liu X, Morency E, Li T, Qin H, Zhang X, Zhang X, et al. Role for PADI6 in securing the mRNA-MSY2 complex to the oocyte cytoplasmic lattices. Cell Cycle. 2017;16:360–6.
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229–49.
Kan R, Yurttas P, Kim B, Jin M, Wo L, Lee B, et al. Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices. Dev Biol. 2011;350:311–22.
Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet. 2019;20:235–48.
Demond H, Anvar Z, Jahromi BN, Sparago A, Verma A, Davari M, et al. A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation. Genome Med. 2019;11:84.
Elbracht M, Mackay D, Begemann M, Kagan KO, Eggermann T. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Hum Reprod Update. 2020;26:197–213.
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, EG110/15–1; 948/32–1 FUGG). This work was supported by the Genomics Facility, a core facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University.
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Eggermann, T., Kadgien, G., Begemann, M. et al. Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-00762-0