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

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