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A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia

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Abstract

Background

Both non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) are pathological conditions characterized by premature and frequently complete gametogenesis failure. Considering that the conserved meiosis I steps are the same between oogenesis and spermatogenesis, inherited defects in meiosis I may result in common causes for both POI and NOA. The present research is a retrospective investigation on an Iranian family with four siblings of both genders who were affected by primary gonadal failure.

Methods

Proband, an individual with NOA, was subjected to clinical examination, hormonal assessment, and genetic consultation. After reviewing the medical history of other infertile members of the family, patients with NOA went through genetic investigations including karyotyping and assessment of Y chromosome microdeletions, followed by Whole exome sequencing (WES) on the proband. After analyzing WES data, the candidate variant was validated using Sanger sequencing and traced in the family.

Results

WES analysis of the proband uncovered a novel homozygote nonsense variant, namely c.118C>T in MSH4. This variant resulted in the occurrence of a premature stop codon in residue 40 of MSH4. Notably, the variant was absent in all public exome databases and in the exome data of 400 fertile Iranian individuals. Additionally, the variant was found to co-segregate with infertility in the family. It was also observed that all affected members had homozygous mutations, while their parents were heterozygous and the fertile sister had no mutant allele, corresponding to autosomal recessive inheritance. In addition, we conducted a review of variants reported so far in MSH4, as well as available clinical features related to these variants. The results show that the testicular sperm retrieval and ovarian stimulation cycles have not been successful yet.

Conclusion

Overall, the results of this study indicate that the identification of pathogenic variants in this gene will be beneficial in selecting proper therapeutic strategies. Also, the findings of this study demonstrate that clinicians should obtain the history of other family members of the opposite sex when diagnosing for POI and/or NOA.

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Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

AMH:

Anti-Müllerian hormone

E2:

Estradiol

FSH:

Follicle stimulating hormone

LH:

Luteinizing hormone

NA:

Not available

NOA:

Non obstructive azoospermia

NR:

Not reported

POI:

Primary ovarian insufficiency

PRL:

Prolactin

SP:

No sperm retrieved after testis biopsy

T:

Testosterone

TSH:

Thyroid stimulating hormone

US:

Ultrasonography

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Acknowledgements

This study is related to the Project No. 43005818 from School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. We appreciate the proband and his family for participating in this study.

Funding

This work was financially supported by Shahid Beheshti University of Medical Sciences Grant No. 43005818.

Author information

Authors and Affiliations

  1. Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Somayeh Hashemi Sheikhshabani

  2. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Somayeh Hashemi Sheikhshabani, Soudeh Ghafouri-Fard & Mir Davood Omrani

  3. Department of Obstetrics and Gynecology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Elham Hosseini

  4. Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mir Davood Omrani

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  1. Somayeh Hashemi Sheikhshabani
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  2. Soudeh Ghafouri-Fard
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  3. Elham Hosseini
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  4. Mir Davood Omrani
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Contributions

Conception and design (SHS and MDO), acquisition of samples and data (SHS and EH), analysis and interpretation of data (SHS, EH and SGF), and manuscript preparation (SHS and SGF). All the authors read and approved the submitted version.

Corresponding author

Correspondence to Mir Davood Omrani.

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The authors declared they have no conflict of interests as defined by Springer, or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the National Research Committee of the Institutional Review Board (IRB), with the approval code of IR.SBMU.MSP.REC.1402.326 and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all of the participants in the study and. Written informed consent for publication of clinical details and clinical images was obtained from the all of the participants in the study.

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Hashemi Sheikhshabani, S., Ghafouri-Fard, S., Hosseini, E. et al. A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia. Mol Biol Rep 51, 68 (2024). https://doi.org/10.1007/s11033-023-09000-4

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