Maternal Effect Mutations: A Novel Cause for Human Reproductive Failure

Abstract

Genetic alterations significantly contribute to the aetiology of reproductive failure and comprise monogenic, chromosomal and epigenetic disturbances. The implementation of next-generation sequencing (NGS) based approaches in research and diagnostics allows the comprehensive analysis of these genetic causes, and the increasing detection rates of genetic mutations causing reproductive complications confirm the potential of the new techniques. Whereas mutations affecting the fetal genome are well known to affect pregnancies and their outcome, the contribution of alterations of the maternal genome was widely unclear. With the recent mainly NGS-based identification of maternal effect variants, a new cause of human reproductive failure has been identified. Maternal effect mutations affect the expression of subcortical maternal complex (SCMC) proteins from the maternal genome, and thereby disturb oocyte maturation and progression of the early embryo. They cause a broad range of reproductive failures and pregnancy complications, including infertility, miscarriages, hydatidiform moles, aneuploidies and imprinting disturbances in the fetus. The identification of women carrying these molecular alterations in SCMC encoding genes is therefore essential for a personalised reproductive and genetic counselling. The diagnostic application of new NGS-based assays allows the comprehensive analysis of these factors, and helps to further decipher these functional links between the factors and their disturbances. A close interdisciplinary collaboration between different disciplines is definitely required to further decipher the complex regulation of early embryo development, and to translate the basic research results into clinical practice.

Zusammenfassung

Genetische Veränderungen tragen wesentlich zur Ätiologie der Unfruchtbarkeit bei. Sie umfassen monogene Erkrankungen sowie Chromosomenanomalien und epigenetische Veränderungen. Der Einsatz von Next-Generation-Sequenzierung (NGS) in der Forschung und Diagnostik hat eine umfassende Analyse der genetischen Ursachen von Reproduktionsversagen ermöglicht, und die steigende Zahl entdeckter genetischer Mutationen, die zu Schwierigkeiten bei der Reproduktion führen, bestätigen das Potenzial dieser neuen Techniken. Es ist zwar bekannt, dass Mutationen, die das fetale Genom beeinflussen, sich auf die Schwangerschaft und das Schwangerschafts-Outcome auswirken, aber inwieweit Änderungen des mütterlichen Genoms sich negativ auswirken, war bislang nicht klar. Die in jüngster Zeit durch NGS ermittelten neuen Maternal-Effekt-Varianten stellen eine neue Ursache für Reproduktionsversagen beim Menschen dar. Maternal-Effekt-Mutationen beeinflussen die Exprimierung von Proteinen des subkortikalen maternalen Komplexes (SCMC) aus dem mütterlichen Genom und verzögern damit die Oozytenreifung bzw. die embryonale Frühentwicklung. Maternal-Effekt-Mutationen sind die Ursache für ein breites Spektrum an reproduktiven Störungen und Schwangerschaftskomplikationen wie Unfruchtbarkeit, Fehlgeburten, Blasenmolen, Aneuploidien und Störungen der genomischen Prägung des Fetus. Die Identifizierung von Frauen mit molekularen Veränderungen in ihren SCMC-kodierenden Genen ist daher unerlässlich für eine personalisierte reproduktive und genetische Beratung. Der Einsatz neuer NGS-basierter Nachweisverfahren in der Diagnostik erlaubt eine umfassende Analyse solcher Faktoren und hilft bei der Entschlüsselung der Funktionszusammenhänge zwischen diesen Faktoren und der jeweiligen Störung. Eine enge interdisziplinäre Zusammenarbeit zwischen Spezialisten verschiedenster Disziplinen ist gefordert, um die komplexe Regulierung der frühen Embryonalentwicklung weiter zu entschlüsseln und die Ergebnisse dieser Grundlagenforschung in die klinische Praxis umzusetzen.

Schlüsselwörter

subkortikaler maternaler Komplex - Maternal-Effekt-Mutation - Fehlgeburten - Blasenmole - Multi-Locus-Imprintingstörung - Next-Generation-Sequenzierung

Keywords

subcortical maternal complex - maternal effect mutation - miscarriages - hydatidiform mole - multilocus imprinting disturbance - next generation sequencing

Publication History

Received: 08 December 2020

Accepted after revision: 19 February 2021

Article published online:
13 July 2021

• References

• 1 Edmonds DK, Lindsay KS, Miller JF. et al. Early embryonic mortality in women. Fertil Steril 1982; 38: 447-453 (PMID: 7117572)
• 2 Choudhury SR, Knapp LA. Human reproductive failure I: immunological factors. Hum Reprod Update 2001; 7: 113-134 DOI: 10.1093/humupd/7.2.113. (PMID: 11284658)
• 3 Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol 2018; 15: 369-384 DOI: 10.1038/s41585-018-0003-3. (PMID: 29622783)
• 4 Yatsenko SA, Rajkovic A. Genetics of human female infertility†. Biol Reprod 2019; 101: 549-566 DOI: 10.1093/biolre/ioz084. (PMID: 31077289)
• 5 Xavier MJ, Salas-Huetos A, Oud MS. et al. Disease gene discovery in male infertility: past, present and future. Hum Genet 2021; 140: 7-19 DOI: 10.1007/s00439-020-02202-x. (PMID: 32638125)
• 6 Robbins SM, Thimm MA, Valle D. et al. 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: 1539-1548 DOI: 10.1007/s10815-019-01499-6. (PMID: 31273585)
• 7 Papas RS, Kutteh WH. A new algorithm for the evaluation of recurrent pregnancy loss redefining unexplained miscarriage: review of current guidelines. Curr Opin Obstet Gynecol 2020; 32: 371-379 DOI: 10.1097/GCO.0000000000000647. (PMID: 32590384)
• 8 Toth B, Wurfel W, Bohlmann M. et al. Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050). Geburtsh Frauenheilkd 2018; 78: 364-381 DOI: 10.1055/a-0586-4568. (PMID: 29720743)
• 9 Page JM, Silver RM. Genetic Causes of Recurrent Pregnancy Loss. Clin Obstet Gynecol 2016; 59: 498-508 DOI: 10.1097/GRF.0000000000000217. (PMID: 27414972)
• 10 ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J. et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018: hoy004
• 11 Barseghyan H, Tang W, Wang RT. et al. Next-generation mapping: a novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis. Genome Med 2017; 9: 90 DOI: 10.1186/s13073-017-0479-0. (PMID: 29070057)
• 12 Elbracht M, Meyer R, Eggermann T. et al. Rational use of genetic tests in internal medicine : Possibilities and limitations of next generation sequencing diagnostics. Internist (Berl) 2018; 59: 756-765 DOI: 10.1007/s00108-018-0457-7. (PMID: 29946883)
• 13 Blackburn HL, Schroeder B, Turner C. et al. Management of Incidental Findings in the Era of Next-generation Sequencing. Curr Genomics 2015; 16: 159-174 DOI: 10.2174/1389202916666150317232930. (PMID: 26069456)
• 14 Begemann M, Rezwan FI, Beygo J. 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 DOI: 10.1136/jmedgenet-2017-105190. (PMID: 29574422)
• 15 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 2021; 29: 575-580 DOI: 10.1038/s41431-020-00762-0. (PMID: 33221824)
• 16 Elbracht M, Mackay D, Begemann M. et al. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Hum Reprod Update 2020; 26: 197-213 DOI: 10.1093/humupd/dmz045. (PMID: 32068234)
• 17 Bilal MY, Katara G, Dambaeva S. et al. Clinical molecular genetics evaluation in women with reproductive failures. Am J Reprod Immunol 2020; e13313 DOI: 10.1111/aji.13313. (PMID: 32710571)
• 18 Eggermann T, Soellner L, Buiting K. et al. Mosaicism and uniparental disomy in prenatal diagnosis. Trends Mol Med 2015; 21: 77-87 DOI: 10.1016/j.molmed.2014.11.010. (PMID: 25547535)
• 19 Begemann M, Zirn B, Santen G. et al. Paternally Inherited IGF2 Mutation and Growth Restriction. N Engl J Med 2015; 373: 349-356 DOI: 10.1056/NEJMoa1415227. (PMID: 26154720)
• 20 Soellner L, Begemann M, Mackay DJ. et al. Recent Advances in Imprinting Disorders. Clin Genet 2017; 91: 3-13 DOI: 10.1111/cge.12827. (PMID: 27363536)
• 21 Sanchez-Delgado M, Riccio A, Eggermann T. et al. Causes and Consequences of Multi-Locus Imprinting Disturbances in Humans. Trends Genet 2016; 32: 444-455 DOI: 10.1016/j.tig.2016.05.001. (PMID: 27235113)
• 22 Mackay DJG, Temple IK. Human imprinting disorders: Principles, practice, problems and progress. Eur J Med Genet 2017; 60: 618-626 DOI: 10.1016/j.ejmg.2017.08.014. (PMID: 28818477)
• 23 Kagan KO, Berg C, Dufke A. et al. Novel fetal and maternal sonographic findings in confirmed cases of Beckwith-Wiedemann syndrome. Prenat Diagn 2015; 35: 394-399 DOI: 10.1002/pd.4555. (PMID: 25641174)
• 24 Monk D, Mackay DJG, Eggermann T. et al. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet 2019; 20: 235-248 DOI: 10.1038/s41576-018-0092-0. (PMID: 30647469)
• 25 Lu X, Gao Z, Qin D. et al. A Maternal Functional Module in the Mammalian Oocyte-To-Embryo Transition. Trends Mol Med 2017; 23: 1014-1023 DOI: 10.1016/j.molmed.2017.09.004. (PMID: 28993030)
• 26 Bebbere D, Masala L, Albertini DF. et al. The subcortical maternal complex: multiple functions for one biological structure?. J Assist Reprod Genet 2016; 33: 1431-1438 DOI: 10.1007/s10815-016-0788-z. (PMID: 27525657)
• 27 Monk D, Sanchez-Delgado M, Fisher R. NLRPs, the subcortical maternal complex and genomic imprinting. Reproduction 2017; 154: R161-R170 DOI: 10.1530/REP-17-0465. (PMID: 28916717)
• 28 Murdoch S, Djuric U, Mazhar B. et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet 2006; 38: 300-302 DOI: 10.1038/ng1740. (PMID: 16462743)
• 29 Parry DA, Logan CV, Hayward BE. et al. Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet 2011; 89: 451-458 DOI: 10.1016/j.ajhg.2011.08.002. (PMID: 21885028)
• 30 Akoury E, Gupta N, Bagga R. et al. Live births in women with recurrent hydatidiform mole and two NLRP7 mutations. Reprod Biomed Online 2015; 31: 120-124 DOI: 10.1016/j.rbmo.2015.03.011. (PMID: 25982095)
• 31 Nguyen NMP, Ge ZJ, Reddy R. et al. Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles. Am J Hum Genet 2018; 103: 740-751 DOI: 10.1016/j.ajhg.2018.10.007. (PMID: 30388401)
• 32 Meyer E, Lim D, Pasha S. et al. Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). PLoS Genet 2009; 5: e1000423 DOI: 10.1371/journal.pgen.1000423. (PMID: 19300480)
• 33 Soellner L, Begemann M, Degenhardt F. et al. Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring. Eur J Hum Genet 2017; 25: 924-929 DOI: 10.1038/ejhg.2017.94. (PMID: 28561018)
• 34 Docherty LE, Rezwan FI, Poole RL. et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat Commun 2015; 6: 8086 DOI: 10.1038/ncomms9086. (PMID: 26323243)
• 35 Sparago A, Verma A, Patricelli MG. 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 DOI: 10.1186/s13148-019-0760-8. (PMID: 31829238)
• 36 Soellner L, Kraft F, Sauer S. et al. Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers. Eur J Hum Genet 2019; 27: 42-48 DOI: 10.1038/s41431-018-0269-1. (PMID: 30218098)
• 37 Qian J, Nguyen NMP, Rezaei M. et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet 2018; 26: 1007-1013 DOI: 10.1038/s41431-018-0141-3. (PMID: 29693651)
• 38 Xu Y, Shi Y, Fu J. et al. Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest. Am J Hum Genet 2016; 99: 744-752 DOI: 10.1016/j.ajhg.2016.06.024. (PMID: 27545678)
• 39 Zheng W, Chen L, Dai J. et al. New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage. J Assist Reprod Genet 2020; 37: 205-212 DOI: 10.1007/s10815-019-01606-7. (PMID: 31664658)
• 40 Cubellis MV, Pignata L, Verma A. et al. Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance. Clin Epigenetics 2020; 12: 139 DOI: 10.1186/s13148-020-00925-2. (PMID: 32928291)
• 41 Demond H, Anvar Z, Jahromi BN. 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 DOI: 10.1186/s13073-019-0694-y. (PMID: 31847873)
• 42 Deveault C, Qian JH, Chebaro W. et al. NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation. Hum Mol Genet 2009; 18: 888-897
• 43 Greenberg MVC, Bourc'his D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol 2019; 20: 590-607 DOI: 10.1038/s41580-019-0159-6. (PMID: 31399642)