Genetic defects in programmed meiotic DNA double-strand break formation and repair in human infertility
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Abstract
In meiosis, the occurrence of programmed DNA double-strand breaks (DSBs) and their repair via homologous recombination are indispensable for homologous chromosome synapsis, crossover formation, and faithful chromosome segregation during gametogenesis. Over the past decade, advances in next-generation sequencing have expanded the spectrum of infertility-associated genes involved in meiotic DSB formation and repair, establishing this pathway as a major genetic determinant of human reproductive disorders. The disruption of these processes impairs homologous recombination and meiotic progression, leading to defective gametogenesis and a wide range of reproductive phenotypes. Clinically, genetic defects affecting meiotic DSB formation and repair have been associated with non-obstructive azoospermia in males, and a broader spectrum of reproductive phenotypes in females, such as premature ovarian insufficiency, recurrent pregnancy loss, fertilization failure, embryonic developmental arrest, recurrent hydatidiform moles, and poor outcomes following assisted reproductive technologies. This review summarizes current advances in genetic defects affecting programmed meiotic DSB formation and repair, with an emphasis on the molecular functions of disease-associated genes, evidence from animal models and genetic studies in humans, sex-dependent genotype-phenotype relationships, and their clinical relevance. Together, these advances provide a foundation for improving molecular diagnosis, genetic counseling, and precision reproductive medicine in patients with unexplained infertility.
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INTRODUCTION
Infertility has emerged as a major global public health challenge, affecting approximately 17.5% of reproductive-aged couples worldwide[1]. Its etiology is highly heterogeneous, encompassing endocrine dysfunction, anatomical abnormalities, immunological disorders, environmental exposures, lifestyle factors, and genetic defects[2]. With the rapid advancement of next-generation sequencing (NGS) and other molecular diagnostic technologies, the contribution of genetic factors to infertility has become increasingly evident, with genetic abnormalities estimated to account for approximately 30%-50% of the cases[2,3].
Meiosis is a specialized cell division process that generates haploid gametes through a single round of DNA replication followed by two consecutive cell divisions. This process ensures the reduction of chromosome number by half and the faithful transmission of genetic information across generations[4]. A central molecular event during meiosis is homologous recombination (HR), which is initiated by programmed DNA double-strand breaks (DSBs)[5]. The formation, localization, and repair of meiotic DSBs are tightly regulated by a highly conserved network of proteins. Defects in these processes can disrupt meiotic progression, impair gametogenesis, and increase the risk of chromosomal abnormalities, ultimately leading to infertility, recurrent pregnancy loss, and embryonic developmental arrest[6].
Over the past decade, advances in human genetics and functional genomics have markedly expanded the landscape of infertility-associated genes involved in meiotic DSB formation and repair. Previous reviews have addressed important aspects of meiotic genetics, including general mechanisms of meiotic recombination or specific infertility phenotypes, whereas the focus on genes involved in programmed meiotic DSB formation and repair in human infertility has remained limited[7-9]. In this review, we summarize the current knowledge on infertility-associated genes involved in programmed meiotic DSB formation and repair, with particular emphasis on their molecular functions, pathogenic mechanisms, genotype-phenotype correlations, and translational implications for molecular diagnosis, genetic counseling, and precision reproductive medicine.
FORMATION AND REPAIR OF MEIOTIC PROGRAMMED DNA DOUBLE-STRAND BREAKS
Programmed DNA DSBs and their subsequent repair via homologous recombination are central events in meiosis that enable homologous chromosome pairing, synapsis, crossover formation, and accurate chromosome segregation [Figure 1][10].
Figure 1. Mechanistic Overview of Programmed Meiotic Double-Strand Breaks (DSBs) Formation, Repair, and Crossover Pathway Choice. Programmed meiotic DSBs are initiated at PRDM9-defined recombination hotspots through recruitment of the SPO11-TOP6BL complex by the pre-DSB recombinosome. Following DSB formation, SPO11-bound DNA ends are processed by the MRE11-RAD50-NBS1 (MRN) complex together with CtIP, generating 3’ single-stranded DNA (ssDNA) overhangs. The exposed ssDNA is initially bound by replication protein A (RPA), while the MEIOB-SPATA22 complex contributes to the stabilization and processing of recombination intermediates. RAD51 and DMC1 are subsequently loaded onto ssDNA and promote homology search and strand invasion into the homologous chromosome. Recombination intermediates may be repaired by synthesis-dependent strand annealing (SDSA), resulting in non-crossover products, or proceed through crossover pathways. Class I crossovers are promoted by ZMM-associated factors, including MSH4-MSH5, HFM1, RNF212, HEI10, and the SHOC1-TEX11-SPO16 complex, which stabilize recombination intermediates and facilitate their maturation into double Holliday junction (dHJ) structures. These intermediates are subsequently resolved primarily by the MutLγ complex composed of MLH1 and MLH3 to generate interference-sensitive class I crossover products. Class II crossovers arise through an alternative, interference-independent pathway involving MUS81-EME1, whereas GEN1 may also contribute to the resolution of meiotic recombination intermediates. The blue and red lines represent chromatids from homologous chromosomes, whereas colored symbols represent key meiotic proteins or protein complexes involved in each step. Solid arrows indicate the major progression of meiotic recombination, and dashed arrows indicate intermediate processing steps. The pathways shown are based largely on studies of mammalian meiosis, particularly in mouse models; direct experimental evidence in humans remains limited for some steps. ZMM: Zip–Mer–Msh proteins; ZZS: Zip2–Zip4–Spo16 complex; CtIP: CtBP-interacting protein. Created in BioRender. yi, S. (2026) https://BioRender.com/48i53yr
Formation of programmed DSBs
Programmed DSBs are generated during meiotic prophase I and serve as initiating events for homologous recombination[8]. Unlike accidental DNA damage, meiotic DSBs occur in defined genomic regions known as recombination hotspots and are tightly regulated both spatially and temporally. Hotspot selection is primarily determined by the coordinated activity of the meiosis-specific DNA-binding protein PRDM9 and chromatin remodeler helicase, lymphoid specific (HELLS)[11-13]. PRDM9 recognizes specific DNA motifs through its zinc-finger domain and catalyzes the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 36 (H3K36me3) in nearby nucleosomes. These epigenetic modifications designate potential recombination hotspots and create a chromatin environment conducive to DSB formation. Subsequently, HELLS and other chromatin-remodeling factors promote local chromatin opening, thereby increasing DNA accessibility and facilitating the recruitment of DSB-forming proteins[14].
DSB formation is directly catalyzed by the SPO11-TOP6BL complex, an evolutionarily conserved topoisomerase VI-like heterotetramer[15]. Precise targeting of this complex to recombination hotspots requires a specialized chromosome axis-associated pre-DSB recombinosome[16]. During meiotic prophase I, IHO1, REC114, and MEI4 assemble into a ternary complex with a 4:4:2 stoichiometry, which subsequently associates with MEI1 and ANKRD31 to form a functional pre-DSB complex. Through interactions between IHO1 and the chromosome-axis protein HORMAD1, this complex anchors the DSB-forming machinery to unsynapsed chromosome axes and promotes the recruitment of SPO11-TOP6BL to PRDM9-defined hotspots, thereby ensuring efficient and accurately positioned formation of DSBs[17,18]. Following recruitment, SPO11-TOP6BL catalyzes the site-specific cleavage of both DNA strands through a Mg2+-dependent, adenosine triphosphate (ATP)-independent transesterification reaction. During this process, SPO11 becomes covalently attached to the 5’ end of the cleaved DNA, generating protein-bound DSB intermediates that trigger meiotic homologous recombination[19,20].
Repair of programmed DSBs
Following DSB formation, high-fidelity repair pathways are rapidly activated to preserve genome integrity and stability. During meiosis prophase I, programmed DSBs generated by SPO11 are predominantly repaired through HR, whereas non-homologous end joining is largely suppressed[21].
DSB repair is initiated by the removal of SPO11-linked DNA ends and resection of DSB termini by the MRE11-RAD50-NBS1 (MRN) complex together with CtBP-interacting protein (CtIP), generating 3’ single-stranded DNA (ssDNA) overhangs. Long-range resection is subsequently extended by bloom syndrome helicase (BLM) helicase along with DNA2 and EXO1[22]. The resulting ssDNA is rapidly coated by replication protein A (RPA) and subsequently replaced by RAD51 and the meiosis-specific recombinase DMC1, with the assistance of mediator proteins including BRCA2, TEX15, MEILB2-BRME1, XRCC2, and ZSWIM7[23,24].
RAD51-DMC1 nucleoprotein filaments promote homology search and strand invasion into homologous chromosomes, generating displacement loop (D-loop) intermediates that serve as the central structures of meiotic recombination. Following repair DNA synthesis, these intermediates are processed via crossover (CO) or non-crossover (NCO) pathways[25]. Most recombination events are resolved as NCOs through synthesis-dependent strand annealing (SDSA) or dissolution by the bloom syndrome helicase-topoisomerase IIIα-RMI1–RMI2 complex (BTR) complex. In contrast, a subset of intermediates is stabilized by Zip-Mer-Msh (ZMM) proteins, including MSH4-MSH5, HFM1, RNF212, and HEI10, and matures into double Holliday junctions (dHJs). These crossover precursors are subsequently resolved by the MutLγ (MLH1-MLH3) complex to generate class I COs, whereas a smaller proportion of class II COs are generated through the MUS81-EME1-dependent pathway. GEN1 may also contribute to the resolution of meiotic recombination intermediates[26-28].
Molecular mechanisms linking aberrant DSB formation and repair to infertility
Defective DSB formation or repair can profoundly disrupt meiotic progression, leading to abnormalities in homologous chromosome synapsis, recombination, and segregation. These defects may result in aneuploid gametes or meiotic arrest, ultimately resulting in infertility. The underlying molecular mechanisms mainly include the following:
(1) Insufficient DSB formation: reduced SPO11 activity or dysfunction of key DSB- forming factors such as IHO1, REC114, and MEI1 may lead to a decreased number of DSBs. Consequently, homologous chromosomes fail to generate sufficient COs and chiasmata to maintain the proper bivalent structure and tension required for accurate chromosome segregation, resulting in chromosome mis-segregation and increased risk of aneuploidy[29].
(2) Aberrant DSB positioning: defects in PRDM9, components of the pre-DSB complex, or chromatin regulatory pathways can impair the spatial distribution of DSB hotspots. This may misdirect the SPO11-TOP6BL complex to inappropriate genomic loci, thereby increasing the risk of aberrant recombination and chromosomal structural abnormalities, such as translocations and insertions[15].
(3) Impaired DSB repair: defects in key recombination factors such as RAD51 and DMC1 compromise homologous recombination repair, thereby leading to persistent DNA breaks, defective synapses, and meiotic arrest. In addition, escape from meiotic checkpoint control may result in chromosome fragmentation or structural aberrations in gametes[30].
GENES INVOLVED IN DSB FORMATION AND REPAIR THAT ARE ASSOCIATED WITH HUMAN INFERTILITY
An increasing number of genes involved in DSB formation and repair have been implicated in human infertility[31]. Genetic variants in these genes may disrupt distinct stages of meiotic recombination, giving rise to a broad spectrum of reproductive phenotypes. Below, we summarize the genes implicated in human infertility according to their functions in meiotic DSB formation and repair. To reflect differences in the strength of available human genetic evidence, genes are further stratified according to the number of independent human families reported to date, with evidence levels assessed separately for male and female infertility [Table 1 and Supplementary Table 1].
Summary of genotype-phenotype associations for genes involved in programmed meiotic DSB formation and repair
| Gene | Molecular function | Mouse knockout phenotype | Males | Females | References | ||||
| Phenotype | Mode of inheritance | Evidence level & | Phenotype | Mode of inheritance | Evidence level & | ||||
| SPO11 | Catalyzes programmed meiotic DSB formation | Both-sex infertility; meiotic arrest/synapsis failure in males; postnatal oocyte loss in females | NOA | AR | Limited | Recurrent blastulation failure | AR | Limited | [35,36] |
| TOP6BL | SPO11 partner required for meiotic programmed DSB formation | Both-sex infertility; meiotic arrest/synapsis failure in males; oocyte maturation failure in females | NOA | AR | Emerging | Hydatidiform mole, recurrent, 4 (OMIM: #618432); Primary infertility | AR | Emerging | [37-40] |
| MEI1 | Pre-DSB factor required for SPO11-dependent meiotic DSB formation | Both-sex infertility; meiotic DSB/synapsis defects with male meiotic arrest; female oocyte loss and segregation defects | Spermatogenic failure 103 (OMIM: #621619) | AR | Confirmed | Hydatidiform mole, recurrent, 3 (OMIM: #618431); Oocyte/zygote/embryo maturation arrest 26 (OMIM: #621620); Embryonic chromosomal abnormalities | AR | Confirmed | [36,37,42-48,50-52] |
| REC114 | REC114-MEI4-IHO1 pre-DSB factor required for meiotic DSB formation | Both-sex infertility; male zygotene-like arrest/synapsis failure with absent DSBs; impaired oocyte development in females | NOA | AR | Emerging | Oocyte/zygote/embryo maturation arrest 10 (OMIM: #619176); POI | AR | Confirmed | [36,37,55-59] |
| MEI4 | Pre-DSB factor regulating meiotic DSB formation and positioning | Both-sex infertility; male zygotene-like arrest/synapsis failure with absent DSBs; female oocyte loss/follicle depletion, POI-like | / | / | / | Embryonic developmental arrest; POI$ | AR; AD$ | Confirmed; Emerging$ | [60-62] |
| IHO1 | Axis-associated pre-DSB factor required for meiotic DSB formation | Both-sex infertility; male pachytene arrest/synapsis failure with absent or severely defective DSBs; female oocyte loss/follicle depletion by 6 weeks | / | / | / | / | / | / | / |
| ANKRD31 | REC114-interacting scaffold-like pre-DSB factor regulating meiotic DSB number, timing and positioning, especially in the PAR | Male infertility; PAR DSB defects with X-Y synapsis failure; female oocyte loss and age-dependent fertility decline | / | / | / | POI | AD | Emerging | [66] |
| HORMAD1 | Unsynapsed-axis HORMA protein regulating meiotic DSB formation, synapsis and prophase I checkpoint signaling | Both-sex infertility; male mid-pachytene arrest/synapsis failure with apoptosis; female synapsis and spindle defects with aneuploid embryos | NOA | AR | Limited | / | / | / | [69] |
| DMC1 | Meiosis-specific recombinase mediating inter-homolog DSB repair | Both-sex infertility; male zygotene arrest/synapsis failure with unrepaired DSBs; female oogenesis arrest and oocyte loss | NOA | AR | Confirmed | POI; DOR | AR | Emerging | [24,36,73-76,78] |
| TEX15 | Recombination mediator required for RAD51/DMC1 loading and meiotic DSB repair | Male infertility with female fertility; male pre-pachytene arrest with defective DSB repair, impaired RAD51/DMC1 loading and synapsis failure | Spermatogenic failure 25 (OMIM: #617960) | AR | Confirmed | / | / | / | [80,84-87] |
| XRCC2 | RAD51 paralog/BCDX2 component required for RAD51/DMC1-mediated meiotic DSB repair | Null mice are embryonic lethal; Xrcc2 p.Leu14Pro mice show male meiotic arrest/azoospermia and female follicle depletion/POI-like ovarian failure | Spermatogenic failure 50 (OMIM: #619145) | AR | Emerging | Premature ovarian failure 17 (OMIM: #619146) | AR | Limited | [82,88,89] |
| ZSWIM7 | SWSAP1-ZSWIM7/Shu complex component supporting RAD51/DMC1 assembly during meiotic DSB repair | Both-sex infertility; male pachytene arrest with defective HR, synapsis failure and apoptosis; female oocyte/follicle loss with POI-like phenotype | Spermatogenic failure 71 (OMIM: #619831) | AR | Confirmed | Ovarian dysgenesis 10 (OMIM: #619834) | AR | Confirmed | [89-95] |
| MEIOB | MEIOB-SPATA22 ssDNA-binding factor required for meiotic HR-mediated DSB repair | Both-sex infertility; male zygotene/pachytene-like arrest with unrepaired DSBs, synapsis failure and absent crossovers; female rapid follicle depletion/POI-like ovarian failure | Spermatogenic failure 22 (OMIM: #617706) | AR | Confirmed | Premature ovarian failure 23 (OMIM: #620686) | AR | Emerging | [50,76,97-103] |
| SPATA22 | MEIOB-interacting ssDNA-binding factor required for meiotic recombination intermediate stability | Both-sex infertility; male zygotene arrest with defective DSB repair, synapsis failure and apoptosis; female follicle depletion/POI-like ovarian failure | Spermatogenic failure 96 (OMIM: #621001) | AR | Limited | Premature ovarian failure 25 (OMIM: #621002) | AR | Limited | [100,104,105] |
| MSH4 | MutSγ component stabilizing crossover-fated recombination intermediates for class I crossover formation | Both-sex infertility; male zygotene-like arrest with synapsis/crossover failure and absent mature sperm; female postnatal oocyte depletion/ovarian atrophy | Spermatogenic failure 2 (OMIM: #108420) | AR | Confirmed | Premature ovarian failure 20 (OMIM: #619938) | AR | Confirmed | [50,59,111-120,126,128] |
| MSH5 | MutSγ subunit that stabilizes crossover-designated meiotic recombination intermediates and promotes class I crossover formation | Both-sex infertility; male zygotene-like arrest with synapsis/crossover failure and azoospermia; female oocyte depletion and ovarian atrophy | Spermatogenic failure 74 (OMIM: #619937) | AR | Confirmed | Premature ovarian failure 13 (OMIM: #617442) | AR | Confirmed | [57,59,76,113,120-124,127] |
| MLH3# | MLH1-MLH3/MutLγ endonuclease required for class I crossover maturation and chiasma formation | Both-sex infertility; male MI arrest/crossover failure; female oocyte aneuploidy and post-fertilization arrest | NOA | AR | Emerging | POI; DOR; RPL; Embryonic arrest | AR | Confirmed | [36,74,129-132] |
| HFM1 | Meiosis-specific ZMM helicase promoting class I crossover formation and complete homologous chromosome synapsis | Both-sex infertility; male meiotic arrest with reduced crossovers and azoospermia; female follicle depletion and ovarian atrophy | NOA, severe oligozoospermia | AR | Confirmed | Premature ovarian failure 9 (OMIM: 615724); Recurrent pregnancy loss; Recurrent androgenetic hydatidiform moles; Preimplantation embryonic arrest | AR | Confirmed | [116,126,135-148] |
| RNF212 | SUMO E3 ligase stabilizing MutSγ-bound recombination intermediates for crossover designation | Both-sex infertility; male metaphase I arrest with crossover failure and azoospermia; female infertility despite normal ovaries and oocyte numbers | Spermatogenic failure 62 (OMIM: #619673) | AR | Limited | / | / | / | [151] |
| SHOC1 | ZZS complex component that binds meiotic recombination intermediates and promotes class I crossover formation | Conventional knockout: embryonic lethal; Germ cell-specific knockout: both-sex infertility with male synapsis/crossover failure and azoospermia, and female follicle depletion | Spermatogenic failure 75 (OMIM: #619949) | AR | Confirmed | / | / | / | [50,154,156-159] |
| TEX11 | Meiosis-specific ZMM factor promoting recombination intermediate processing, class I crossover formation, and homologous chromosome synapsis | Male infertility with pachytene arrest, asynapsis, reduced crossovers, and azoospermia; females largely fertile | Spermatogenic failure, X-linked 2 (OMIM: #309120) | XLR | Confirmed | / | / | / | [50,155,157,160-169] |
| SPO16 | Component of the evolutionarily conserved ZZS complex with SHOC1 and TEX11; recruited by SHOC1 to stabilize early recombination intermediates and facilitate their progression toward double Holliday junction (dHJ) formation and class I crossover maturation | Spo16-deficient mice exhibit severe defects in homologous chromosome synapsis, failure of crossover formation, and meiotic arrest at a zygotene-like or early pachytene-like stage, resulting in infertility | NOA | AR | Limited | POI | AR | Limited | [157,170] |
Genes involved in meiotic DSB formation
SPO11 and TOP6BL
SPO11 and TOP6BL (TOPOVIBL) constitute the catalytic core responsible for meiotic DSB formation[15,32]. Knockout mouse models of either gene exhibit infertility in both sexes, which is characterized by defective DSB formation, failed homologous chromosome synapsis, meiotic arrest, and extensive germ-cell depletion[33,34]. However, evidence differs between these two genes in humans. A single homozygous missense variant, c.556G>A (p.Glu186Lys), was reported in two brothers with non-obstructive azoospermia (NOA) and maturation arrest[35]. More recently, biallelic SPO11 variants were reported in female patients with recurrent blastulation failure, thereby expanding the reproductive phenotypic spectrum associated with SPO11 deficiency[36]. In contrast, biallelic TOP6BL variants have been identified in both sexes and are associated with NOA in men and recurrent hydatidiform mole (RHM) in women, establishing TOP6BL as a gene responsible for infertility in both sexes[37-40].
MEI1
MEI1 is an essential component of the meiosis-specific pre-DSB recombinosome and is required for efficient meiotic DSB formation and homologous chromosome synapsis[7]. Mei1-/- mice closely phenocopy Spo11-/- mice, exhibiting complete infertility caused by defective DSB formation and meiotic arrest[41]. Studies in humans have shown that biallelic MEI1 variants are a cause of infertility in both sexes. Male patients consistently present with NOA resulting from spermatocyte-stage meiotic arrest, whereas affected females exhibit a broader reproductive spectrum, including RHM, recurrent implantation failure (RIF), preimplantation embryonic arrest (PREMBA), and embryonic chromosomal abnormalities[37,42-52].
REC114, MEI4, and IHO1
REC114, MEI4, and IHO1 form a core trimeric subcomplex of the pre-DSB recombinosome, which is required for recruitment and stabilization of the SPO11-TOP6BL catalytic machinery on chromosome axes. Homozygous knockout mouse models of Rec114, Mei4, and Iho1 are infertile in both sexes[17,53,54]. All three mutants share a core meiotic phenotype characterized by defective programmed DSB formation and impaired homologous chromosome synapsis. In males, these defects result in early spermatocyte arrest accompanied by extensive apoptosis, whereas females exhibit severe oocyte depletion and near-complete loss of primordial and primary follicles.
Among these genes, REC114 is the best-characterized infertility-associated gene in humans. Biallelic pathogenic variants have been repeatedly identified in women with recurrent androgenetic complete hydatidiform moles, abnormal fertilization with multiple pronuclei, and early embryonic developmental arrest[37,55]. In males, REC114 deficiency has been consistently associated with NOA characterized by defective meiotic recombination and zygotene-stage arrest[36,37,55-58]. More recently, biallelic pathogenic REC114 variants have also been associated with premature ovarian insufficiency (POI), further expanding the phenotypic spectrum of REC114-related female infertility[59].
Recent studies established that MEI4 is a female infertility gene associated with a spectrum of reproductive phenotypes. The first MEI4 variants were identified in four unrelated families with female infertility that was predominantly characterized by preimplantation embryonic arrest. Six homozygous or compound heterozygous missense variants were shown to impair the DNA-binding capacity of MEI4, and knock-in mouse models have recapitulated the human phenotype, demonstrating defective oogenesis and female infertility[60,61]. More recently, Wang et al. identified three heterozygous loss-of-function variants of MEI4 in 1,530 women with POI. Functional analyses demonstrated that these variants impaired meiotic DSB formation by disrupting stabilization of the MEI4-REC114 subcomplex. The corresponding mouse models exhibited oocyte depletion, follicular loss, and early embryonic arrest, supporting a haploinsufficiency mechanism underlying MEI4-associated reproductive disorders[62].
To date, no pathogenic IHO1 variants have been reported in humans. Complete loss of Iho1 causes infertility in both male and female mice, whereas disruption of the C-terminal HORMAD1-interacting motif reduces DSB formation and results in subfertility[63]. These findings suggest IHO1 is a strong candidate gene for infertility in humans.
ANKRD31
ANKRD31 is a key regulator of the number, timing, and genomic distribution of meiotic DSBs, particularly in the pseudoautosomal region[64,65]. Ankrd31-/- male mice are sterile, whereas females exhibit reduced fertility accompanied by oocyte depletion and POI-like phenotypes[65]. However, genetic evidence in humans is limited. Heterozygous loss-of-function variants were identified in women with POI[66]. Functional studies have shown that these variants impair the interaction between ANKRD31 and REC114, supporting a haploinsufficiency mechanism and implicating ANKRD31 insufficiency in human ovarian dysfunction[66].
HORMAD1
HORMAD1 is a meiosis-specific HORMA-domain protein that localizes to unsynapsed chromosome axes and plays a critical role in meiotic DSB formation, homologous chromosome synapsis, and meiotic checkpoint surveillance via its interaction with IHO1 and other chromosome-axis components[67,68]. Hormad1 deficiency in mice causes infertility in both sexes, which is characterized by defective homologous chromosome synapsis and impaired meiotic progression[68].
Evidence in humans is currently limited to a single consanguineous family carrying a homozygous loss-of-function variant, in which affected males presented with NOA caused by spermatocyte meiotic arrest[69]. Functional studies have demonstrated that this variant abolishes the nuclear localization of HORMAD1, resulting in cytoplasmic retention of the mutant protein and meiotic arrest of primary spermatocytes[69]. Although clinical evidence remains limited, these findings support a conserved role of HORMAD1 in human male fertility.
Genes involved in meiotic DSB repair
DMC1
DMC1 is a meiosis-specific RecA-family recombinase that catalyzes homologous strand invasion during meiotic homologous recombination and is therefore indispensable for meiotic DSB repair[70,71]. Dmc1-/- mice are infertile in both sexes owing to defective homologous chromosome synapsis, meiotic arrest, and extensive germ-cell loss. Specifically, male mice exhibit spermatocyte arrest at the zygotene-to-pachytene transition, whereas female mice undergo severe oocyte depletion as a result of extensive apoptosis during meiotic prophase I[72]. In humans, clinical genetic evidence has firmly established DMC1 as an autosomal recessive infertility gene affecting both males and females. Biallelic pathogenic variants have been identified in men with NOA and in women with POI or diminished ovarian reserve (DOR)[73-77]. Functional studies have consistently demonstrated that these variants impair DMC1 recombinase activity, resulting in defective homologous recombination and meiotic DSB repair. Interestingly, female patients carrying loss-of-function variants may retain residual ovarian function and are capable of producing mature oocytes, suggesting that humans and mice differ in terms of the requirement for DMC1 during oogenesis[75]. Subsequent studies have further expanded the mutational spectrum of DMC1-associated infertility[24,36,78]. Collectively, these findings establish DMC1 as the central recombinase mediating meiotic DSB repair and underscore its essential role in human fertility.
TEX15, XRCC2, and ZSWIM7
TEX15, XRCC2, and ZSWIM7 function as key accessory factors that promote RAD51-DMC1 recombinase loading, nucleoprotein filament assembly and stabilization, homologous chromosome synapsis, and efficient meiotic DSB repair. Studies involving mouse models have provided evidence of essential roles for all three genes in meiotic recombination, although the phenotypic severity differs among them. Tex15 deficiency in mice results in defective meiotic DSB repair, impaired homologous chromosome synapsis, and spermatogenic arrest, leading to complete male infertility, whereas female fertility is largely preserved[79,80]. In contrast, conventional Xrcc2 knockout mice are embryonically lethal. Pathogenic knock-in models and Zswim7-null mice exhibit defective homologous recombination, impaired chromosome synapsis, meiotic arrest, and infertility in both sexes[81-83].
Genetic studies in humans have provided evidence supporting the critical roles of these genes in fertility. Biallelic TEX15 variants have been recurrently identified in men with phenotypes ranging from severe oligozoospermia to NOA, establishing TEX15 as one of the most frequently implicated meiosis-specific genes underlying spermatogenic failure[80,84-87]. XRCC2 has been implicated in infertility affecting both sexes, with a homozygous c.41T>C (p.Leu14Pro) variant identified in patients with NOA and POI[82,88]. Functional analyses, including studies in knock-in mouse models, demonstrated that this variant disrupts meiotic DSB repair and homologous chromosome synapsis, confirming the pathogenic role of XRCC2 deficiency. Likewise, biallelic ZSWIM7 variants have been implicated in both male and female infertility. Affected males present with NOA characterized by spermatocyte maturation arrest and defective meiotic recombination, whereas affected females develop POI associated with primary amenorrhea, absent pubertal development, and prepubertal ovaries and uterus[89-95].
MEIOB and SPATA22
MEIOB and SPATA22 form a meiosis-specific heterodimer that cooperates with the RPA complex to stabilize resected ssDNA, thereby protecting recombination intermediates and promoting homologous chromosome synapsis, crossover formation, and efficient meiotic DSB repair[25]. Meiob-/- and Spata22-/- mice display highly similar phenotypes, including defective homologous recombination and chromosome
MSH4, MSH5, MLH3, HFM1, RNF212, SHOC1, and TEX11: the ZMM pathway and core factors in class I crossover formation
The ZMM pathway comprises a functionally coordinated network of pro-crossover factors that promote the maturation of recombination intermediates into interference-sensitive class I crossovers.
Originally identified in Saccharomyces cerevisiae, canonical ZMM proteins include Zip, Mer, and Msh, whose mammalian functional counterparts comprise SYCP1, SHOC1, TEX11, SPO16, HFM1, MSH4, MSH5, RNF212, and HEI10. Acting downstream of these proteins, the MutLγ complex (MLH1-MLH3) resolves designated double Holliday junctions into mature class I crossovers. Disruption of the ZMM pathway impairs crossover maturation and redirects most DSB repair events to the non-crossover pathway, leaving only a small proportion of class II crossovers generated through the MUS81-dependent pathway. This significantly reduces crossover numbers and compromises chromosome segregation[106]. Accordingly, biallelic variants of ZMM genes have been associated with a broad spectrum of reproductive disorders, including NOA, POI, recurrent pregnancy loss, and recurrent hydatidiform moles.
MSH4, MSH5, and MLH3
MSH4 and MSH5 form the meiosis-specific MutSγ heterodimer, which stabilizes recombination intermediates and designates crossover sites, whereas the MLH1-MLH3 (MutLγ) complex acts downstream as the endonuclease that mediates crossover resolution[107,108]. Msh4-/-, Msh5-/-, and Mlh3-/- mice are infertile in both sexes. Msh4/Msh5 deficiency causes defective homologous chromosome synapsis and early meiotic arrest, whereas Mlh3 deficiency primarily disrupts class I crossover formation, leading to chromosome missegregation, metaphase I arrest in males, and defective oocyte maturation in females[109,110].
In humans, biallelic MSH4 and MSH5 variants have already been established as causes of NOA in men and POI in women[50,57,59,76,111-127]. MSH4 variants have also been associated with DOR, suggesting that they impair both oocyte quantity and quality[128]. Interestingly, a heterozygous MSH4 missense variant has been linked to moderate oligozoospermia in a male carrier, whereas female heterozygotes remained fertile, raising the possibility of dosage-dependent effects on male fertility[114]. Recent genetic studies in humans have implicated the biallelic loss-of-function variants of MLH3 in male infertility. Homozygous frameshift variants have been identified in men with spermatogenic failure or NOA, providing further evidence that the disruption of MLH3 impairs meiotic crossover formation in humans[74,129,130]. In females, biallelic MLH3 variants have been associated with a broader spectrum of reproductive phenotypes, including POI, DOR, recurrent pregnancy loss (RPL), and recurrent embryonic arrest[36,131,132].
HFM1
HFM1 encodes a meiosis-specific SF2 DNA helicase that is predominantly expressed in germ cells and promotes class I crossover formation by stabilizing early recombination intermediates, facilitating heteroduplex extension, and supporting homologous chromosome synapsis[133]. Hfm1-/- mice are infertile in both sexes, characterized by gonadal hypoplasia, incomplete homologous chromosome synapsis, and markedly reduced crossover formation. In males, spermatocytes are arrested at diakinesis and undergo apoptosis, resulting in azoospermia. Females have smaller ovaries with reduced numbers of follicles and corpora lutea and only infrequent ovulation, consistent with a POI-like phenotype[133,134]. Genetic studies in humans have established that biallelic HFM1 variants cause diverse reproductive disorders. In men, biallelic pathogenic variants are associated with phenotypes ranging from severe oligozoospermia to NOA. In
RNF212
RNF212 is a dosage-sensitive SUMO E3 ligase that cooperates antagonistically with the ubiquitin ligase HEI10 to regulate crossover designation and maturation by stabilizing the MutSγ complex at selected recombination sites[149,150]. Rnf212-/- mice are infertile in both sexes despite largely normal homologous chromosome synapsis. Male mutants exhibit > 90% reduction in crossovers, metaphase I arrest, and azoospermia, whereas females retain morphologically normal ovaries but are infertile because of severe crossover failure[149]. However, genetic evidence in humans is limited. A homozygous truncating RNF212 variant was identified in two brothers with NOA characterized by normal meiotic entry but markedly reduced crossover formation, increased univalent chromosomes, and complete metaphase I arrest, emerging as the first evidence that RNF212 deficiency causes human male infertility[151].
SHOC1, TEX11, and SPO16
SHOC1, TEX11, and SPO16 form the evolutionarily conserved mammalian Zip2–Zip4–Spo16 (ZZS) complex that stabilizes early recombination intermediates following strand invasion and promotes their maturation into interference-sensitive class I crossovers[152]. Mouse models have supported an essential role of the ZZS complex in meiotic recombination. Although conventional Shoc1-null mice are embryonic lethal, hypomorphic and germ cell-specific knockout models demonstrate severe defects in homologous chromosome synapsis, crossover formation, and meiotic progression[153,154]. Similarly, Spo16-null mice exhibit severe defects in homologous chromosome synapsis and meiotic progression, which lead to meiotic arrest at the zygotene-like or early pachytene-like stage, impaired crossover formation, and reproductive failure in both males and females[152]. In mice, Tex11 deficiency in males (Tex11-/Y) results in reduced crossover formation, metaphase I arrest, and infertility, whereas Tex11-/- females remain fertile but exhibit reduced litter size and impaired crossover formation[155].
Genetic evidence in humans implicates SHOC1 and TEX11 in male infertility. Multiple biallelic loss-of-function SHOC1 variants, including homozygous and compound heterozygous truncating mutations, have been identified in men with spermatogenic maturation arrest and NOA, establishing SHOC1 deficiency as a cause of human spermatogenic failure[50,154,156-159]. In contrast, TEX11 is an X-linked meiosis-specific gene and is one of the best-established monogenic causes of idiopathic NOA. Numerous hemizygous pathogenic TEX11 variants have been reported in men with spermatogenic failure. Functional studies have demonstrated that these variants impair meiotic DSB repair, homologous chromosome synapsis, and crossover maturation, leading to spermatocyte arrest and azoospermia[50,155,157,160-169]. Human evidence for SPO16-associated infertility remains limited. A homozygous splice-altering variant (c.160+8A>G) was identified in a woman with POI and functionally shown to disrupt splicing, while a homozygous frameshift variant (c.266del, p.Leu89Trpfs*15) was subsequently reported in an infertile man[157,170]. To date, there have been no reports establishing a convincing association between SHOC1 or TEX11 variants and female infertility. The discrepancy between mouse models and genetic evidence in humans may reflect species-specific differences in meiotic regulation, sex-dependent tolerance to meiotic defects, and limited ascertainment of patients with reproductive disorders.
SEX-DEPENDENT GENOTYPE-PHENOTYPE RELATIONSHIPS
Although most genes involved in programmed meiotic DSB formation and repair are expressed in both male and female germ cells, pathogenic variants often produce strikingly different clinical manifestations in the two sexes. In males, these variants predominantly cause NOA, particularly meiotic arrest-associated NOA (MA-NOA)[171,172]. In contrast, females exhibit a much broader phenotypic spectrum, including POI, DOR, oocyte maturation defects, fertilization failure, embryonic developmental arrest, embryonic aneuploidy, RHM, RPL, and poor outcomes following assisted reproductive technologies (ART)[173,174].
This sexual dimorphism reflects fundamental differences in meiotic timing, checkpoint surveillance, germ-cell developmental dynamics, and reproductive physiology[4]. During spermatogenesis, meiosis begins after puberty and proceeds continuously with highly stringent quality-control mechanisms. Defects in DSB formation, homologous recombination, or crossover formation readily activate the pachytene checkpoint, leading to the apoptotic elimination of defective spermatocytes[175]. In addition, male meiosis requires an accurate pairing and recombination of X and Y chromosomes within pseudoautosomal regions, imposing an additional constraint on meiotic chromosome organization[176]. Consequently, pathogenic variants that affect early meiotic recombination frequently cause arrest of spermatogenic maturation and complete infertility[8]. In contrast, female meiosis begins during fetal development, with oocytes entering meiosis and subsequently being arrested at the dictyate stage around birth. Compared with spermatogenesis, oogenesis exhibits greater tolerance to certain recombination defects. Although severe impairment of the DSB pathway similarly triggers meiotic arrest and accelerated oocyte depletion, partial defects may still permit oocytes to progress through meiosis despite reduced crossover numbers or increased chromosome segregation errors[177]. Moreover, as human oocytes subsequently remain arrested at the dictyate stage for years or even decades before ovulation, prolonged meiotic arrest may increase their vulnerability to chromosome instability, and unrepaired or improperly repaired meiotic defects can further compromise chromosome stability and developmental competence[178]. Beyond sex-dependent biological differences, genotype-phenotype relationships are also influenced by variant-specific functional consequences, inheritance pattern, and the specific stage of meiotic recombination at which gene function is disrupted[8]. Hypomorphic variants with residual activity may permit partial meiotic progression, whereas null variants or defects affecting critical early meiotic processes are more likely to cause severe gametogenic failure. However, substantial phenotypic variability remains, reflecting the complex interplay among genetic dosage, residual protein function, and biological context[7,8].
GENETIC TESTING STRATEGIES AND CLINICAL IMPLICATIONS
Genetic testing should be considered in individuals with phenotypes indicative of meiotic dysfunction, including NOA, POI, RPL, recurrent ART failure, and unexplained embryonic developmental abnormalities. Disease-associated gene panels provide cost-effective screening of established infertility genes, whereas whole-exome sequencing (WES) or whole-genome sequencing enables broader variant detection and facilitates future data reanalysis when initial testing is inconclusive.
Importantly, defects in meiotic DSB formation and repair may result in distinct reproductive consequences between males and females. Therefore, the interpretation of pathogenic variants in meiotic DSB genes should incorporate sex-dependent genotype-phenotype relationships to provide more accurate prognostic information for reproductive counseling. In addition, the molecular function of the affected gene, the stage at which meiosis was disrupted, and variant severity, including residual protein activity, should be integrated into individualized risk assessment. For males with NOA, pathogenic variants in programmed meiotic DSB genes may provide prognostic information for testicular sperm retrieval. Recent multicenter studies suggest that patients with NOA carrying pathogenic variants in early meiotic genes, including SPO11, MEI1, TEX11, and MSH4, have a very low likelihood of sperm retrieval via micro-testicular sperm extraction. In contrast, individuals with variants in some genes, such as MLH3, may retain residual spermatogenesis and occasionally achieve sperm retrieval[179]. These findings highlight the potential value of gene-specific molecular diagnosis in guiding treatment selection and reproductive counseling, although larger cohorts are needed to validate these genotype-phenotype associations. For females, genetic diagnosis may provide important information for reproductive planning and risk anticipation[180]. Identification of pathogenic variants in meiotic DSB-related genes associated with ovarian dysfunction or impaired oocyte competence may prompt earlier assessment of the ovarian reserve and consideration of fertility preservation options before a substantial decline in reproductive potential. For individuals undergoing ART, genetic findings may also facilitate counseling regarding expected reproductive outcomes and the potential risks of impaired oocyte quality, fertilization failure, or early embryonic developmental abnormalities. This information may support individualized reproductive strategies, including the consideration of embryo genetic evaluation when clinically appropriate.
CONCLUSION AND PERSPECTIVES
Programmed meiotic DNA DSB formation and repair constitute the molecular foundation of homologous recombination, faithful chromosome segregation, and genome integrity during meiosis. The widespread application of NGS has considerably expanded the repertoire of DSB-associated genes implicated in human infertility, enabling more accurate molecular diagnosis while providing new insights into the mechanisms underlying meiotic failure[181].
Despite these advances, the genetic basis of infertility remains unclear in a substantial proportion of patients. Although this review focuses on genes directly involved in programmed meiotic DSB formation and repair, other infertility-associated genes involved in meiotic checkpoint activation, chromosome segregation, and oocyte maturation also contribute substantially to reproductive failure, but are not comprehensively covered here. Recent studies have shown that the diagnostic yield of genetic testing in patients with oocyte and early embryo competence defects is only approximately 13.2%-23.1%, indicating that many disease-causing genes and molecular mechanisms remain unidentified[132,182]. Moreover, current genetic studies have largely relied on WES, which may fail to detect clinically relevant variants in non-coding regions, mosaic variants, structural variants, polygenic contributions, or epigenetic alterations. Additionally, the interpretation of newly identified variants remains challenging, particularly for newly proposed mechanisms or genes with limited genetic evidence in human studies. Accurate variant classification requires the integration of multiple lines of evidence, including population data, computational prediction, functional validation, segregation analysis, and phenotype-genotype correlation, following established American College of Medical Genetics and Genomics (ACMG)/ Association for Molecular Pathology (AMP) guidelines. Furthermore, the mechanisms underlying variable expressivity and sex-specific phenotypes remain poorly understood[2]. Addressing these challenges may require the integration of larger and ethnically diverse patient cohorts, whole-genome and long-read sequencing, artificial intelligence -assisted gene discovery, and high-throughput functional validation using clustered regularly interspaced short palindromic repeats -based models[183]. Together, these complementary approaches will accelerate the discovery of novel infertility genes, improve the interpretation of variants of uncertain significance, refine genotype-phenotype correlations, and deepen our understanding of the molecular mechanisms governing human meiosis.
Nevertheless, translating these discoveries into effective therapies remains challenging. Unlike postnatal genetic disorders, defects in meiotic DSB formation and repair arise during prophase I of meiosis. In females, this developmental program is completed during fetal life, leaving little opportunity for therapeutic intervention after diagnosis[178]. In the foreseeable future, the greatest clinical impact of identifying DSB-associated defects will lie in early molecular diagnosis, genetic counseling, reproductive risk assessment, and individualized reproductive management, thereby laying the foundation for precision reproductive medicine. As our understanding of meiotic DSB biology continues to evolve, integration of genomic, functional, and clinical evidence will be critical for bridging the gap between gene discovery and clinical practice, ultimately enabling precision diagnosis and personalized reproductive care.
DECLARATIONS
Acknowledgments
The Graphical Abstract was created using BioRender.com (Publication License No. YC2ADR0XH4 https://BioRender.com/nxww604).
Authors’ contributions
Collected relevant papers and drafted the manuscript: Sui Y
Participated in revising the review, provided financial support for this review: Li S
Involved in the initiation and revision of this review: Sui Y, Yin Y, Ma T, Chen Y, Li S
Finalized the manuscript: Li S, Chen Y
All authors read and approved the final manuscript.
Availability of data and materials
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AI and AI-assisted tools statement
During the preparation of this manuscript, the AI tool ChatGPT (version GPT-5.5, released 2026-04-23) was used solely for language editing. The tool did not influence the study design, data collection, analysis, interpretation, or the scientific content of the work. All authors take full responsibility for the accuracy, integrity, and final content of the manuscript.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (82471687) and the Shanghai Hospital Development Center Foundation (SHDC12026127).
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Copyright
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Supplementary Materials
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Sui Y, Yin Y, Ma T, Chen Y, Li S. Genetic defects in programmed meiotic DNA double-strand break formation and repair in human infertility. J Transl Genet Genom. 2026;10:604-25. https://dx.doi.org/10.20517/jtgg.2026.97
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