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A genomics approach to females with infertility and recurrent pregnancy loss

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Abstract

Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women with recurrent pregnancy loss and no offspring from spontaneous pregnancies (RPL, n = 61) and those who never achieved clinical pregnancy and were referred for in vitro fertilization [primary infertility (PI), n = 14]. Whole-exome sequencing revealed candidate variants in 14, which represents 43% of those with PI and 13% of those with RPL. These include variants in previously established female infertility-related genes (TLE6, NLRP7, FSHR, and ZP1) as well as genes with only tentative links in the literature (NLRP5). Candidate variants in genes linked to primary ciliary dyskinesia (DNAH11 and CCNO) were identified in individuals with and without systemic features of the disease. We also identified variants in genes not previously linked to female infertility. These include one homozygous variant each in CCDC68, CBX3, CENPH, PABPC1L, PIF1, PLK1, and REXO4, which we propose as candidate genes for infertility based on their established biology or compatible animal models. Our study expands the contribution of single genes to the etiology of PI and RPL, improves the precision of disease classification at the molecular level, and offers the potential for future treatment and development of human genetics-inspired fertility regulators.

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Acknowledgements

We thank the study subjects for their enthusiastic participation. We thank the Genotyping and Sequencing Core Facilities at KFSHRC for their technical support.

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Author notes

  1. Sateesh Maddirevula, Khalid Awartani, and Serdar Coskun have contributed equally.

Authors and Affiliations

  1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    Sateesh Maddirevula, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem & Fowzan S. Alkuraya

  2. Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    Khalid Awartani, Latifa F. AlNaim & Saad Alhassan

  3. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center and College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Serdar Coskun

  4. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Fowzan S. Alkuraya

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  1. Sateesh Maddirevula
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  2. Khalid Awartani
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  3. Serdar Coskun
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Correspondence to Fowzan S. Alkuraya.

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439_2020_2143_MOESM1_ESM.xlsx

Table S1. Clinical evaluation details on all patients (n=75). * for variant information refer Table 1. APA; anticardiolipin (anticardiolipin IgM Antibody (less than 12.5); Anticardiolipin IgA (<12.0 U/mL); Anticardiolipin IgG (<15.0 U/mL); Anti- B2 glycoprotein I (<20 U/mL for IgG and/or IgM); Anti- phosphatidylserine antibodies IgM (less than 24.9); ANA (antinuclear antibodies) (1.4-1.6); Thyroid (0.4-4.0 mIU/L); Prolactin (<25 ng/mL); Protein C (0.5 – 1.24IU); Protein S (0.6 – 1.40IU); Antithrombin (80-120IU); Homocystine (5-15IU); Factor V + MTFHR (Normal – heterozygous – homozygous). APC; activated protein C (negative – positive). Prothrombin (12–13 seconds). Fibrinogen (1.4 – 4.4IU). Lipoprotein A: normal values <30 mg/dL (milligrams per deciliter), or 1.7 mmol/L. N/A not available. All these tests were performed as a part routine clinical workup in a clinical lab accredited by College of American Pathologist (CAP). (XLSX 21 kb)

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Maddirevula, S., Awartani, K., Coskun, S. et al. A genomics approach to females with infertility and recurrent pregnancy loss. Hum Genet 139, 605–613 (2020). https://doi.org/10.1007/s00439-020-02143-5

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