Genetic profiling of azoospermic men to identify the etiology and predict reproductive potential
Open accessAbstract
Purpose: To identify germline mutations related to azoospermia etiology and reproductive potential of surgically retrieved spermatozoa, and to investigate the feasibility of predicting seminiferous tubule function of nonobstructive azoospermic men by transcriptomic profiling of ejaculates. Materials and methods: Sperm specimens were obtained from 30 men (38.4 ± 6 years) undergoing epididymal sperm aspiration for obstructive azoospermia (OA, n = 19) acquired by vasectomy, or testicular biopsy for nonobstructive azoospermia (NOA, n = 11). To evaluate for a correlation with azoospermia etiology, DNAseq was performed on surgically retrieved spermatozoa, and cell-free RNAseq on seminal fluid (n = 23) was performed to predict spermatogenesis in the seminiferous tubule. Results: Overall, surgically retrieved sperm aneuploidy rates were 1.7% and 1.8% among OA and NOA cohorts, respectively. OA men carried housekeeping-related gene mutations, while NOA men displayed mutations on genes involved in crucial spermiogenic functions (AP1S2, AP1G2, APOE). We categorized couples within each cohort according to ICSI clinical outcomes to investigate genetic causes that may affect reproductive potential. All OA-fertile men (n = 9) carried mutations in ZNF749 (sperm production), whereas OA-infertile men (n = 10) harbored mutations in PRB1, which is essential for DNA replication. NOA-fertile men (n = 8) carried mutations in MPIG6B (stem cell lineage differentiation), whereas NOA-infertile individuals (n = 3) harbored mutations in genes involved in spermato/spermio-genesis (ADAM29, SPATA31E1, MAK, POLG, IFT43, ATG9B) and early embryonic development (MBD5, CCAR1, PMEPA1, POLK, REC8, REPIN1, MAPRE3, ARL4C). Transcriptomic assessment of cell-free RNAs in seminal fluid from NOA men allowed the prediction of residual spermatogenic foci. Conclusions: Sperm genome profiling provides invaluable information on azoospermia etiology and identifies gene-related mechanistic links to reproductive performance. Moreover, RNAseq assessment of seminal fluid from NOA men can help predict sperm retrieval during testicular biopsies.
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Male infertility is associated with variations in APOE genotypes.
“Beyond LPG, recently the increased studies have showed that male infertility is associated with variations in APOE genotypes.4,5”
From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [5]
An APOE frameshift mutation was identified in testicular biopsies from patients with nonobstructive azoospermia.
“Meanwhile, Cheung et al5 reported the identification of an APOE frameshift mutation in testicular biopsies from patients with nonobstructive azoospermia.5”
From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [5]
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Self-citation
- Authors
- Cheung, S., Ng, L., Xie, P., Kocur, O., Elias, R., Schlegel, P., Rosenwaks, Z., & Palermo, G. D.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Palermo, Gianpiero D.
- Venue
- Journal of Assisted Reproduction and Genetics
- Published
- 2024-02-26
- Volume
- 41
- Issue
- 4
- Pages
- 1111-1124
- ISSN
- 0740-7769 (ISSN-L)
- 1058-0468
- 1573-7330
- PMC
- PMC11052749
- OpenAlex
- W4392165630
- Cited by
- 9
- References
- 51
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Assisted Reproduction and Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
- Keywords
- azoospermia, non-obstructive azoospermia, obstructive azoospermia, germline mutations, sperm aneuploidy, spermatogenesis, cell-free RNA, epididymal sperm aspiration, vasectomy, fertility, ICSI outcomes, PRB1
- MeSH terms
- Genetic Profile, Adult, Humans, Infertility, Male, Male, Middle Aged, Mutation, Spermatogenesis, Spermatozoa, Testis, Sperm Retrieval, Azoospermia
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