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Maternal exome analysis for the diagnosis of oocyte maturation defects and early embryonic developmental arrest

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  • Antonio Capalbo
  • Silvia Buonaiuto
  • Matteo Figliuzzi
  • Gianluca Damaggio
  • Laura Girardi
  • Silvia Caroselli
  • Maurizio Poli
  • Cristina Patassini
  • Murat Cetinkaya
  • Beril Yuksel
  • Ajuna Azad
  • Marie Louise Grøndahl
  • Eva R Hoffmann
  • Carlos Simón
  • Vincenza Colonna
  • Semra Kahraman
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RESEARCH QUESTION: Can a methodology be developed for case selection and whole-exome sequencing (WES) analysis of women who are infertile owing to recurrent oocyte maturation defects (OOMD) and/or preimplantation embryo lethality (PREMBL)?

DESIGN: Data were collected from IVF patients attending the Istanbul Memorial Hospital (2015-2021). A statistical methodology to identify infertile endophenotypes (recurrent low oocyte maturation rate, low fertilization rate and preimplantation developmental arrest) was developed using a large IVF dataset (11,221 couples). Twenty-eight infertile women with OOMD/PREMBL were subsequently enrolled for WES on their genomic DNA. Pathogenic variants were prioritized using a custom-made bioinformatic pipeline set to minimize false-positive discoveries through resampling in control cohorts (the Human Genome Diversity Project and 1343 whole-exome sequences from oocyte donors). Individual single-cell RNA sequencing data from 18 human metaphase II (MII) oocytes and antral granulosa cells was used for genome-wide validation. WES and bioinformatics were performed at Igenomix and the National Research Council, Italy.

RESULTS: Variant prioritization analysis identified 265 unique variants in 248 genes (average 22.4 per sample). Of the genes harbouring high-impact variants 78% were expressed by MII oocytes and/or antral granulosa cells, significantly higher than for random sample of controls (odds ratio = 5, Fisher's exact P = 0.0004). Seven of the 28 women (25%) were homozygous carriers of missense pathogenic variants in known candidate genes for OOMD/PREMBL, including PATL2, NLRP5 (n = 2),TLE6, PADI6, TUBB8 and TRIP13. Furthermore, novel gene-disease associations were identified. In fact, one woman with a low oocyte maturation rate was a homozygous carrier of high-impact variants in ENSA, an essential gene for prophase I meiotic transition in mice.

CONCLUSIONS: This analytical framework could reveal known and new genes associated with isolated recurrent OOMD/PREMBL, providing essential indications for scaling this strategy to larger studies.

Original languageEnglish
JournalReproductive BioMedicine Online
Issue number3
Pages (from-to)508-518
Number of pages11
Publication statusPublished - Sep 2022

Bibliographical note

Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

    Research areas

  • ATPases Associated with Diverse Cellular Activities, Animals, Cell Cycle Proteins/genetics, Exome, Female, Humans, Infertility, Female/genetics, Mice, Oocytes/pathology, Oogenesis, Tubulin/genetics, Whole Exome Sequencing

ID: 79448918