Diminished ovarian reserve (DOR) is a common cause of female infertility, affecting approximately 10% of women seeking fertility treatment. It is characterized by a reduced quantity and quality of ovarian follicles that compromises the reproductive potential and often precedes premature ovarian insufficiency. Although environmental, endocrine, and age-related factors contribute to disease development, a substantial proportion of cases remain genetically unexplained, limiting opportunities for early diagnosis, genetic counseling, and targeted interventions.

In this Genes & Diseases study, researchers from Chongqing Medical University identified cyclin N-terminal domain containing 1 (CNTD1) as a previously unrecognized genetic determinant of DOR and investigated the molecular and functional consequences of a novel homozygous truncating mutation in this meiosis-associated gene.

The researchers performed whole-exome sequencing in a patient diagnosed with DOR and identified a homozygous splice-site mutation in CNTD1 (c.823-2A>G). To establish the pathogenicity of this variant, they combined transcript sequencing from the patient's primary leukocytes with a minigene splicing assay, demonstrating that the mutation induced complete skipping of exons six and seven, the partial deletion of the 3′UTR, and the abnormal retention of a partial segment of intron five, ultimately resulting in a substantial base pair deletion that generates a truncated CNTD1 mutant protein.

To investigate the physiological significance of CNTD1 deficiency, the researchers generated a CRISPR/Cas9-mediated Cntd1 knockout mouse model. Female knockout mice exhibited markedly reduced ovarian size and a profound depletion of primordial and growing follicle pools, indicating premature exhaustion of the ovarian reserve. Histological analyses demonstrated severe impairment of folliculogenesis, consistent with the infertility-associated phenotype observed in the patient. These in vivo findings confirmed that CNTD1 plays an essential role in maintaining ovarian function and preserving the follicular reserve required for female fertility. Furthermore, the study established that CNTD1 is predominantly expressed within oocytes rather than surrounding granulosa cells, highlighting its intrinsic role in female germ cell maturation.

Mechanistically, the study demonstrated that functional CNTD1 is indispensable for successful meiotic crossover formation through its interaction with PRR19. Structural and functional analyses further revealed that the CNTD1 truncated protein cannot interact with PRR19, resulting in disrupted meiotic progression, impaired chromosome recombination, and compromised oocyte development, ultimately leading to accelerated depletion of ovarian follicles. These findings established the molecular basis by which the identified mutation disrupts normal meiotic function.

By integrating human genetic analysis with molecular validation and animal modeling, the researchers established a direct causal relationship between CNTD1 dysfunction and DOR. The study also extends previous observations from experimental animal models by providing the first clinical evidence linking CNTD1 deficiency to human reproductive disease.

In summary, this investigation establishes the CNTD1 c.823-2A>G mutation as a novel genetic determinant of DOR, providing critical mechanistic insights into the essential role of the CNTD1-PRR19 regulatory axis in maintaining the ovarian reserve. These findings expand the genetic landscape of DOR, improve understanding of the molecular mechanisms governing ovarian reserve maintenance, and highlight CNTD1 as a promising candidate for genetic diagnosis and reproductive risk assessment in women with unexplained ovarian insufficiency.

Reference
Title of the original paper: Identification of the homozygous truncating mutation in CNTD1 as a novel genetic cause of diminished ovarian reserve

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101900

Funding Information:
National Natural Science Foundation of China (No. 82302083)
Natural Science Foundation of Chongqing, China (No. CSTB2025NSCQ-GPX0281)
National Reserve Talents Program in the Health Sector of Chongqing (China) (No. HBRC2024015)
CQMU Program for Youth Innovation in Future Medicine (China) (No. W0207)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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