Genome variant characterization, population stratification, and systemic analysis for precision medicine in patients with ovarian failure

• Autores: Ismael Henarejos Castillo
• Directores de la Tesis: José Remohí Giménez (dir. tes.), Patricia Díaz Gimeno (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2024
• Idioma: español
• Tribunal Calificador de la Tesis: Nuria Paricio Ortiz (presid.), Francisco García García (secret.), Christian Becker (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
• Materias:
  • Ciencias de la vida
    • Biología humana
      • Genética humana
    • Fisiología humana
      • Fisiología de la reproducción
    • Biología molecular
    • Biología vegetal (botánica)
  • Ciencias médicas
    • Ciencias clínicas
      • Genética clínica
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• Resumen

  • Ovarian failure, a complex disorder, typically involves a rapid depletion of the follicular reserve before natural menopause. It affects 1% of women under 40 and 0.1% under 30. While 90% of cases are idiopathic, 10-25% may result from genetic factors, accounting for at least 50% of inter-individual variability in menopausal age. Despite advancements in next-gen sequencing, the pathogenesis of ovarian failure remains poorly understood, emphasizing the need for biomarker research for early diagnosis.

    In this Ph.D. dissertation, focusing on the 90% idiopathic cases, the goal is to deepen understanding of genomic, genetic, and functional causes and classify ovarian failure into genomic subtypes based on variant profiles Objective: Characterize ovarian failure's molecular heterogeneity, discover new genes involved, and understand underlying molecular mechanisms.

    Methodology: Conducted case-control SNV screening using whole exome sequencing of 118 ovarian failure cases and 32 controls. Pseudo-controls from IGSR and GnomAD aided in variant prioritization. Variants were used to differentiate and classify the population, prioritizing genes affected by significant variant presence. Genes were validated in vivo using Drosophila models to assess variant impact on reproduction.

    Results: Identified a genomic profile of 66 variants associated with ovarian failure. Cases were stratified into two subtypes, distinguishable with 98% and 93.3% accuracy. Eighteen genes, including AK2, CDC27, CFTR, CTBP2, KMT2C, and MTCH2, showed higher variant presence in ovarian failure (FDR<0.05). Silencing/knockout of these genes in Drosophila reduced fertility.

    Conclusion(s): Described various genomic origins for ovarian failure impacting biological processes, such as DNA repair, mitosis/meiosis progression, chromatin organization, and mitochondrial activities. These findings may advance personalized reproductive medicine, improving clinical management and fertility preservation with potential non-invasive, blood-based biomarkers for young women.