Genetic Infertility - An Approach

A diagnostic, therapeutic and reproductive approach to chromosomal and monogenic causes of male and female infertility: sex chromosome aneuploidies, Y chromosome microdeletions, structural rearrangements, congenital absence of the vas deferens, genes underlying spermatogenic failure and sperm morphological defects, the FMR1 premutation and premature ovarian insufficiency genes.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definitions and scope

Infertility is defined as the inability of a sexually active couple not using contraception to achieve spontaneous pregnancy within 12 months; it is primary when the couple has never conceived and secondary when a previous pregnancy has occurred [3]. The definition concerns the couple, not the individual, with practical genetic consequences: severe oligozoospermia may be compatible with paternity when the partner is young and highly fertile, and this previously led to coexistence within a family of fertile and infertile men carrying the same Y chromosome deletion being interpreted as “variable penetrance” [2]. European Association of Urology (EAU) guidelines distinguish “idiopathic” male infertility, where no explanatory factor is found despite abnormal semen parameters (30–40% of men), from “unexplained” couple infertility, where semen parameters and partner assessment are normal (20–30% of couples) [3]. Oxford Desk Reference, published in 2017, placed male factor as the predominant cause in 20–26% of couples and unexplained infertility in 25–30% of fully investigated couples, and reported that approximately 14% of the UK reproductive-age population was affected, in an Aberdeen study cited by the authors [4, 39].

This article addresses genetic infertility through a cross-cutting approach organised by patient sex and mechanism. In males, the scope includes sex chromosome aneuploidies (Klinefelter syndrome and variants), the 46,XX male, 45,X/46,XY mosaicism and structural Y rearrangements, AZF (AZoospermia Factor) region microdeletions and partial gr/gr deletion, Robertsonian and reciprocal translocations and inversions, obstructive azoospermia due to congenital absence of the vas deferens associated with CFTR or ADGRG2, spermatogenic failure genes responsible for non-obstructive azoospermia (NOA) and genes underlying sperm morphological and motility defects, including DNAH1 and multiple morphological abnormalities of the sperm flagella (MMAF). In females, it includes Turner syndrome, FMR1 premutation-associated premature ovarian insufficiency (POI; FXPOI, fragile X-associated primary ovarian insufficiency), isolated and syndromic POI genes such as MCM8 and MCM9, genetic causes of primary amenorrhoea and oocyte and embryonic defects emerging only during assisted reproduction. The general finding of genetic male and female infertility is addressed jointly because it shares the same entities and sources [2, 28, 29]. Turner syndrome, Klinefelter syndrome and X polysomies, fragile X syndrome, cystic fibrosis, primary ciliary dyskinesia, Kallmann syndrome and recurrent pregnancy loss of genetic cause are addressed only in their reproductive aspects.

Semen terminology follows the World Health Organization (WHO) manual. EAU uses the 5th-edition classification — oligozoospermia below 16 million/mL, asthenozoospermia below 32% progressive motility and teratozoospermia below 4% normal forms — and notes that the 6th edition, July 2021, no longer defines this subdivision, although the panel considers it clinically useful [3]. Severe oligozoospermia, below 5 million/mL, is associated with a higher incidence of obstruction and genetic abnormalities; cryptozoospermia is distinguished from azoospermia by centrifuging semen at 3000 g for 15 minutes and examining the pellet [3]. Obstructive azoospermia (OA) results from blockage of seminal ducts with preserved spermatogenesis, whereas NOA reflects testicular production failure. Numerical thresholds in genetic testing guidelines refer to concentration (million/mL), although since the 2010 manual total count per ejaculate has been preferred, for which data in deletion carriers are lacking [34]. Historical definitions in older texts (oligozoospermia below 20 million/mL, normal morphology ≥30%) do not correspond to current reference values [39].

POI is defined by the 2024 European Society of Human Reproduction and Embryology (ESHRE), American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproductive Life (CRE-WHiRL) and International Menopause Society (IMS) guideline as loss of ovarian activity before 40 years, with amenorrhoea or irregular cycles, elevated gonadotrophins and low oestradiol; the guideline recommends “premature ovarian insufficiency” rather than “premature ovarian failure” and excludes cessation between 40 and 44 years, termed early menopause [5]. In earlier texts, POI appears as “premature ovarian failure” (POF), with an FSH threshold above 20 IU/L [40].

1.2. Historical overview and molecular milestones

The link between the Y chromosome long arm and spermatogenesis was formalised through designation of AZF regions and consolidated through sequencing of the male-specific Y region (MSY). Kuroda-Kawaguchi and colleagues (2001) showed that the most common AZFc deletion removes approximately 3.5 Mb between b2 and b4 amplicons through recombination between nearly identical repeats [2]. Repping and colleagues (2002) demonstrated partial overlap of AZFb and AZFc regions, and deletions came to be defined by their flanking palindromes [2]. European Academy of Andrology (EAA) and European Molecular Genetics Quality Network (EMQN) laboratory recommendations appeared in 1999, 2004 and 2013 and were replaced in 2023 by a “state of the art” revision changing extension markers and incorporating the first human Y telomere-to-telomere assembly, completed in late 2022 [34].

Among autosomal and X-linked genes, early milestones were family reports or small series. Sun and colleagues (1999) described a de novo 4-base-pair deletion in the USP9Y splice donor in an azoospermic man; Miyamoto and colleagues (2003) reported a single-base deletion in SYCP3 in 2 of 19 men with NOA and maturation arrest; Dam and colleagues (2007) associated SPATA16 with globozoospermia in a consanguineous family; Dieterich and colleagues (2007) identified AURKC in macrozoospermia [9]. In 2014, Ben Khelifa and colleagues used homozygosity mapping in 20 North African individuals with primary infertility due to impaired motility and a mosaic of flagellar morphological abnormalities and found homozygous DNAH1 variants, encoding an inner dynein arm heavy chain, in 5 of 18 index cases (28%); the article established the MMAF concept and showed that infertility may be the only manifestation of a ciliary defect [41]. Yatsenko and colleagues (2015) described X-linked TEX11 in 7 of 289 azoospermic men (2.4%) and 5 of 33 with meiotic arrest (15%) [9].

In females, Perrault syndrome was described in 1951 as the association of bilateral sensorineural deafness and ovarian dysfunction in 46,XX women [11]. Classification of blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) into type I (with POI) and type II (ocular only), proposed by Zlotogora in 1983, is now considered insufficient to represent phenotypic variability [12]. The first BMP15 POI report (Di Pasquale 2004) described heterozygous sisters, but the inheritance model was revised to biallelic loss of function [9]. Caburet and colleagues (2014) associated STAG3 with POI in a consanguineous family [9]. Large-scale exome studies, such as that of Ke and colleagues (2023) in 1030 Chinese women, and the first GeneReviews devoted to MCM8 and MCM9, published in June 2026, mark the shift from candidate gene studies to genomic analysis [10, 25].

Assisted reproduction changed the clinical meaning of these diagnoses. Preimplantation sex determination for X-linked diseases was first performed in 1990, the first child following preimplantation diagnosis for cystic fibrosis was born in 1992, and ICSI enabled paternity using ejaculated or surgically retrieved sperm in men with extreme oligozoospermia or azoospermia [2, 42]. Since then, genetic diagnosis has moved beyond explaining infertility to have prognostic value (probability of retrieving sperm) and implications for transmitting the cause to offspring [34].

1.3. Guidelines and reference documents

Current normative sources are the 2026 EAU sexual and reproductive health guidelines, male infertility chapter (limited update of the 2025 edition, with literature search to 25 May 2025) [3]; the joint American Urological Association (AUA) and ASRM male infertility diagnosis and treatment guideline, published in 2020 and amended in 2024 [6]; 2023 EAA/EMQN recommendations for molecular Y microdeletion diagnosis [34]; the 2024 ESHRE/ASRM/CRE-WHiRL/IMS POI guideline, with 145 recommendations [5]; the 2024 international Turner syndrome guideline [43]; the first EAA Klinefelter syndrome guidelines (2021), endorsed by the European Society of Endocrinology [44]; ESHRE PGT Consortium good practice recommendations for structural and numerical aberrations (2020) [36]; and the American College of Medical Genetics and Genomics (ACMG) technical standard for fragile X laboratory testing (2021 revision) [26]. No ESHRE guideline specific to male infertility exists, and consulted sources identified no ACMG male infertility guideline. Clinical validity of male infertility genes is systematised by the 2021 International Male Infertility Genomics Consortium (IMIGC) review [8].

2. Molecular Genetics and Pathophysiology

2.1. Overall genetic architecture

Genetic infertility is a heterogeneous set of mechanisms converging on four final phenotypes: absent gamete production, insufficient gamete numbers, gametes structurally or functionally unable to fertilise or sustain embryonic development, and transport duct obstruction. Aggregated data from 11 publications cited by EAU, comprising 9,766 infertile men, show chromosomal abnormalities in 5.8% (sex chromosomes 4.2%, autosomes 1.5%), versus 0.38% of 94,465 male neonates (sex chromosomes 0.14%, autosomes 0.25%); below 5 million/mL incidence is approximately tenfold higher than in the population, predominantly due to structural autosomal abnormalities, while sex chromosome abnormalities predominate in NOA [3]. The IMIGC systematic review, with evidence to July 2020 and a clinical validity scale scored from 0 to 17, assessed approximately 600 genes and classified 104 with moderate (45), strong (27) or definitive (48) evidence for 120 male infertility or genitourinary abnormality phenotypes; of these relationships, 67 were endocrine or reproductive system syndromes, 36 isolated infertility and 17 syndromic infertility; inheritance was autosomal recessive in 68, autosomal dominant in 38, X-linked in 12 and Y-linked in 2 [8]. At that review date, only approximately 4% of infertile men received a genetic diagnosis and 60–70% remained unexplained; the number of MMAF genes with robust evidence had risen from 5 in 2018 to 15 by mid-2020, and there were 15 robust genes for NOA and oligozoospermia [8]. The AUA/ASRM guideline states that GeneCards lists over 3600 genes associated with male infertility, reflecting associations of widely varying nature rather than clinical validity [6].

In females, known architecture is similarly diverse. In the exome study of 1030 Chinese women with POI (120 primary and 910 secondary amenorrhoea), 195 pathogenic or likely pathogenic (P/LP) variants were found in 59 of 95 known genes in 193 patients (18.7%); 80.3% of findings were monoallelic, 12.4% biallelic and 7.3% multi-heterozygous; meiotic and homologous recombination repair genes represented 48.7% of solved cases (with HFM1, SPIDR and BRCA2 among the most frequent), and mitochondrial (AARS2, ACAD9, CLPP, COX10, HARS2, MRPS22, PMM2, POLG, TWNK), metabolic (GALT) and autoimmune (AIRE) genes 22.3% [10]. The most frequent individual genes were NR5A1 and MCM9 (each 11/1030, 1.1%), and loss-of-function variant burden analysis against 5000 controls added 20 candidate genes, raising total yield to 242/1030 (23.5%) [10]. Predominantly monoallelic findings in genes whose causality was established in recessive families require cautious interpretation of these results' true contribution, and the authors themselves acknowledge that heterozygous variant causality is sometimes uncertain [10].

2.2. Sex chromosome aneuploidies and rearrangements in males

Klinefelter syndrome (47,XXY) is the most common sex chromosome aneuploidy and the most frequent chromosomal cause of male infertility and hypogonadism [3, 39]. The supernumerary X results from nondisjunction in paternal or maternal meiosis I, or in meiosis II, and the maternal age effect increases the risk from approximately 1/2500 live births at 33 years to 1/300 at 43 years, according to data cited by OXF [32, 33]. The variants 48,XXXY, 48,XXYY and 49,XXXXY have more severe presentations, and 46,XY/47,XXY mosaicism is associated with a milder phenotype and a greater likelihood of germ cells [3, 33]. Reproductive pathophysiology consists of progressive degeneration of the germinal epithelium: puberty begins normally, but midway through puberty the testes involute and hypergonadotrophic hypogonadism develops with small, firm testes [3, 32]. The focal spermatogenesis persisting in some patients arises from euploid germ cells, which explains why the great majority of children born to fathers with non-mosaic Klinefelter syndrome are chromosomally normal [32].

The 46,XX male (46,XX testicular disorder of sex development [DSD]) has a prevalence of approximately 1/20 000 males; approximately 80% are SRY-positive, due to abnormal de novo X–Y exchange transferring SRY to the X [30, 39]. SRY-negative cases result from small copy-number variants (CNVs) in SOX3 or the upstream SOX9 regulatory region (a gene desert up to approximately 2 Mb that may escape chromosomal microarray [CMA] if the laboratory does not report the region), specific heterozygous NR5A1 variants such as p.(Arg92Trp), or variants in a specific WT1 subdomain [30]. Without Y AZF regions, there is no spermatogenesis and testicular sperm retrieval is impossible [6, 34].

45,X/46,XY mosaicism spans a spectrum from Turner syndrome to mixed gonadal dysgenesis and phenotypically normal males; in prenatally diagnosed series approximately 90% are males with normal genitalia (72 of 75 in one series; 42 of 47, 89.4%, in another), but some boys later developed dysgenetic testes, infertility and Turner features, and the proportion of 45,X blood or fibroblast cells does not predict phenotype [45]. Dysgenetic gonads carry gonadoblastoma risk [35, 45]. Structural Y rearrangements, such as isodicentric Yp [idic(Yp)], preserve SRY (male phenotype) but lose AZF region copies, causing azoospermia; so-called Yq “terminal deletions” are generally complex pseudodicentric rearrangements, mitotically unstable, generating mosaic 45,X lines and potentially disrupting pseudoautosomal genes such as SHOX, with short stature [2, 39]. Age-related Y loss complicates interpretation: Y hypoploidy in lymphocytes increases from 0.05% below 15 years to 1.34% at 76–80 years, and low-level mosaicism should be interpreted according to age and phenotype [45].

2.3. Y chromosome microdeletions

MSY contains 156 transcription units (78 protein-coding) and three sequence classes: single-copy X-degenerate; X-transposed, 99% identical to X; and ampliconic, with >99.9%-identical repeats organised in palindromes and nine testis-expressed gene families [34]. Non-allelic homologous recombination (NAHR) between repeats in the same orientation causes complete deletions, explaining their recurrence and predictable breakpoints [34]. After Klinefelter syndrome, AZF microdeletions are the second most recurrent genetic cause of male infertility [34].

Table sources: [2, 3, 34]. Relative frequencies differ between guidelines because they derive from different series; OXF reported approximately 4 Mb for AZFc, replaced by the reference sequence measurement of 3.5 Mb [2, 39].

AZFa contains two single-copy genes with X paralogues, USP9Y (USP9X) and DDX3Y (DDX3X); DDX3Y translation occurs only in the male germline, mainly spermatogonia [2]. Complete USP9Y deletion was found in a normozoospermic man, his brother and father, and the few gene-specific partial AZFa deletions described in over 2000 analysed patients affected USP9Y with phenotypes from azoospermia to normozoospermia, so USP9Y is now considered a spermatogenic “fine-tuner” [9, 34]. Loss-of-function DDX3Y variants were recently described as an azoospermia cause, placing DDX3Y as AZFa's essential spermatogenic factor; Sertoli-cell-only (SCO) syndrome in complete deletion requires loss of both genes [2, 34]. In AZFc deletions, loss of all four DAZ copies does not prevent some spermatogenesis, attributed to compensation by the autosomal paralogue DAZL (chromosome 3), acting as a “backup gene”; no equivalent autosomal copies exist for AZFa and AZFb genes, explaining prognostic differences [2]. Deletions detected as AZFabc are probably associated with an abnormal karyotype, such as a 46,XX male or Y isochromosome [34]. AZFa and AZFc duplications do not appear to affect fertility, and b1/b3 and b2/b3 deletions are benign copy-number variations [2].

The gr/gr deletion removes half of AZFc gene content and acts as a population-dependent risk factor. In a multiethnic study of 20,000 Y chromosomes, it was present in 1 in 41 males and almost doubled severe spermatogenic failure risk, explaining approximately 2%; five meta-analyses estimated odds ratios (ORs) between 1.8 and 2.5, and in Spanish and Italian cohorts (944 patients and 1044 normozoospermic men) risk was fourfold higher [34]. The deletion is fixed without apparent effect in haplogroups D2b, Q3 and Q1, frequent in Japan and parts of China, so interpretation in Asian men requires haplogroup determination; GeneReviews reports approximately 25% carriage in Japanese men [2, 34]. In a Mediterranean cohort of 497 men with testicular germ cell tumours and 2030 controls, gr/gr was associated with an OR of 3.1 (95% confidence interval [CI] 1.4–7.0) for this tumour [34]. Compensatory duplications may occur, and expansion to complete AZFc deletion in the next generation has been proposed without sufficient data [2, 34].

2.4. Autosomal chromosomal rearrangements and X;autosome translocations

Robertsonian translocations involve the acrocentric chromosomes 13, 14, 15, 21 and 22; the most common are rob(13q14q) and rob(14q21q), with a population frequency of approximately 1/1000 carriers (rob(13q14q) approximately 1/1300), arising de novo mainly in oogenesis [46]. In meiosis, alternate segregation produces normal or balanced gametes and adjacent segregation produces disomic or nullisomic gametes; the main phenotypic risks are trisomy 21 or 13 and uniparental disomy (UPD) of chromosomes 14 or 15 through trisomy rescue [46]. In men, the effect on spermatogenesis is measured by fluorescence in situ hybridisation (FISH) on sperm: Robertsonian translocation carriers produce 3.4–36% unbalanced sperm and reciprocal translocation carriers 47.5–81%, versus a mean disomy of approximately 6.7% in 46,XY men [39]. der(13;14) carriers are overrepresented 5- to 10-fold among infertile couples with oligozoospermia, although a series by Engels (2008) found male infertility in 11% of carriers, a value similar to more recent population data, suggesting that the enrichment depends on the mode of ascertainment [46]. Robertsonian translocations are the most common balanced translocations and are associated with infertility, pregnancy loss and unbalanced offspring [6]. Balanced rearrangements explain approximately 1.5% of men with NOA or oligozoospermia [2]. The segregation of reciprocal translocations, the risk of viable imbalance and their relationship with recurrent pregnancy loss constitute a separate topic [47].

In female carriers of a balanced X;autosome translocation, the normal X is usually inactivated and both parts of the translocated X remain active, through selection against functional disomy; when the breakpoint lies in the critical regions Xq13–q22 or Xq22–q27, the carrier is at risk of gonadal dysgenesis, primary amenorrhoea or POI [48]. Elsewhere, OXF describes a critical region Xq26.2–Xq28 for ovarian function and, in relation to Turner syndrome, an Xq13–q26 region whose sparing allows pregnancy; the formulations differ in their boundaries but converge in locating on the long arm of the X genes necessary for follicle maintenance [35, 40]. Men with an X;autosome translocation are infertile [48]. Ring chromosomes are sporadic in 99% of cases, are associated with male subfertility and, in familial cases, are maternally transmitted in 90%; transmission by a mosaic parent may give rise to a more severe phenotype in the offspring, who inherit the ring without mosaicism [49].

2.5. Congenital absence of the vas deferens: CFTR and ADGRG2

CFTR (7q31.2) encodes a cyclic adenosine monophosphate (cAMP)-dependent chloride channel [6]. EAU locates the gene at “7p”, a guideline error [3, 6]. Congenital bilateral absence of the vas deferens (CBAVD) results from defective fetal Wolffian structure development and is almost constant in males with cystic fibrosis (CF), occurring in approximately 97% [28, 50]. In men with CBAVD without clinical CF, the rule is compound heterozygosity for a severe loss-of-function variant and a mild or non-CF-causing variant, such as the 5T allele; residual protein, approximately 10% of normal, prevents clinical CF but not abnormal Wolffian duct development [2, 28]. Isolated CBAVD is the most common CFTR-related disorder (CFTR-RD), defined by biallelic variants without other CF manifestations; a small percentage develop adult respiratory or pancreatic disease [28]. AUA/ASRM reports CFTR variants in up to 80% of men with CBAVD, 20% with unilateral absence (CUAVD) and 21% with idiopathic epididymal obstruction; in a study of 198 men, 34% with idiopathic obstruction carried a CFTR variant [6]. Sources differ on the biallelic proportion in CBAVD (70% in OXF, up to 80% with at least one variant in AUA/ASRM), depending on analysis extent [6, 39]. Beyond obstruction, CFTR acts in spermatogenesis: lower expression in CBAVD is associated with lower count, motility, bicarbonate sensitivity and fertilisation rates [28].

The poly-T tract in historical intron 8 (current intron 9), also called IVS8-5T, regulates exon 9 splicing [6, 51]. Alleles 7T and 9T are benign; 5T produces approximately 50% full-length transcript, versus approximately 75% with 7T or 9T, and when in cis with 12 or 13 TG repeats in the adjacent tract (c.1210-34TG[11_13]), full-length transcript falls to approximately 25%, with a greater adverse effect [28]. 5T/5T homozygosity may also cause CAVD [2]. Phase of p.(Arg117His) with the poly-T tract modulates phenotype: in cis with 5T and with p.(Phe508del) on the other allele, it usually associates with non-classical pancreatic-sufficient CF, and in cis with 9T, with CBAVD without respiratory symptoms [50]. 5T allele normalisation is inconsistent between tools: GeneReviews uses NM_000492.3:c.1210-12T[5]; VariantValidator on MANE Select NM_000492.4 corrects to c.1210-12_1210-6T[5], warning that repeat description should be used only as annotation, and returns a genomic description (g.117548629_117548635T[6]) not corresponding to the transcript description [28, 51]. This article uses the transcript description with historical IVS8-5T designation, without genomic description.

CBAVD unexplained by CFTR has at least two origins. Approximately 20% of men with CBAVD have unilateral or bilateral renal agenesis due to a very early (before 9 weeks) defect of the entire mesonephric duct, unrelated to CFTR [39]. In men with both kidneys and no CFTR explanation, X-linked ADGRG2 is the main cause: Patat and colleagues (2016) found hemizygous truncating variants in 4 of 26 CFTR-negative CBAVD men without renal agenesis, and in a French cohort 26% (5/19) with CAVD, 0–1 CFTR variant and both kidneys had an ADGRG2 variant [9]. ADGRG2 is estimated to explain approximately 2% of all CAVD and approximately 20% unexplained by CFTR; ADGRG2- or CFTR-related CAVD rarely coexists with a solitary kidney, whereas CAVD with unilateral renal agenesis usually has neither cause [9]. The Orphanet-derived GenCC entry lists autosomal recessive inheritance for ADGRG2, inherited from generic CBAVD mapping, which is a mapping error; OMIM records X-linked inheritance [9].

2.6. Monogenic spermatogenic failure and non-obstructive azoospermia

NOA affects 0.4–2% of men and approximately 10% of infertile male cohorts [52]. Most known genes act in meiosis, synaptonemal complex formation, DNA recombination and repair, or spermatogonial survival and differentiation; loss of function leads to three histological patterns — SCO, maturation arrest (in spermatogonia, spermatocytes or spermatids) and hypospermatogenesis — with prognostic value for surgical retrieval [2, 3]. The GEMINI consortium, with 11 centres (including Porto and Lisbon), sequenced exomes of 1011 men with spermatogenic failure and found a plausible recessive Mendelian cause in approximately 20% (178/924 men with NOA, single-nucleotide variants and small insertions/deletions only); a two-stage burden test with 2072 cases and 11,587 fertile controls gave additional support to 21 mainly autosomal genes clustering into molecular subforms according to expression in testicular single-cell RNA sequencing [52].

Table sources: [8, 9, 13, 25, 53].

TEX11 illustrates the necessary caution. The gene encodes a meiosis-specific ZZS complex protein (ZIP2-ZIP4-SPO16), necessary for homologous synapsis and class I crossovers; disease manifests only in hemizygotes and is usually inherited from a phenotypically unaffected heterozygous mother [9]. A recurrent in-frame deletion of exons 10–12 (historically c.652del237bp) had no effect in a mouse model, and 2025 in vitro data question pathogenicity, precluding its treatment as a diagnosis [9]. SYCP3 presents a different problem: the dominant-negative effect of the original deletion (historical 643delA, truncating the C-terminal coiled-coil domain) was not replicated in Belgian, Spanish and Turkish series, and its association with recurrent pregnancy loss in women (2/26 in one series) was also unreplicated [9]. DMRT1 is a gonad-specific transcription factor repressing STRA8 and FOXL2 and activating SOHLH1; rare DM-domain variants show a burden effect in men with spermatogenic failure, and variants near DMRT1 are associated with testicular germ cell tumours in genome-wide association studies [9]. NR5A1, encoding steroidogenic factor 1 (SF-1), causes a 46,XY spectrum from complete gonadal dysgenesis with Müllerian structures to isolated male infertility with severe oligozoospermia or azoospermia, and in 46,XX causes POI and, rarely, testicular or ovotesticular DSD; adrenal insufficiency is rare [9, 13]. Sources differ on SRY contribution to complete 46,XY gonadal dysgenesis: 10–15% in 2022 GeneReviews, 15–20% of XY women in 2017 OXF, which added that approximately 80% had no known aetiology [4, 13]. DHX37 (20% of 46,XY DSD and approximately 20% of testicular regression syndrome), MAP3K1 (10–18%), DHH (with peripheral neuropathy in some patients) and DMRT1 complete the genetic differential of 46,XY gonadal dysgenesis [13].

2.7. Sperm morphological and motility defects

Qualitative sperm defects, sometimes with preserved counts, constitute the group with the highest diagnostic yield: NGS may diagnose up to approximately 50% of MMAF cases [7, 8]. DNAH1 (MANE NM_015512.5) causes the spermatogenic failure form SPGF18, classified as definitive by ClinGen, with autosomal recessive inheritance: severe asthenozoospermia with short, coiled, bent, irregular or absent flagella, loss of the central microtubule pair and axonemal disorganisation with loss of the inner dynein arms [9, 41, 51]. Although DNAH1 is expressed in other ciliated cells, infertility was the only symptom observed in the founding series, and ClinGen classifies the evidence for primary ciliary dyskinesia (PCD37) as limited, so a DNAH1 result in an infertile man does not equate to a diagnosis of primary ciliary dyskinesia [9, 41]. Other MMAF genes with definitive evidence are CFAP43, CFAP44 and CFAP251; with strong evidence, CFAP65, CFAP69, DNAH17, SPEF2 and TTC29; with moderate evidence, ARMC2, CFAP91, FSIP2, QRICH2 and SEPTIN12 (the latter dominantly inherited) [8]. The primary ciliary dyskinesia genes DNAH1, DNAH10 and SPEF2 may present as isolated male infertility, and the structure shared by the flagellum and the motile cilium explains the frequent male subfertility in PCD [29].

Macrozoospermia (large-headed, irregular, multiflagellated sperm, with approximately 100% abnormal forms) results from meiosis I arrest due to biallelic AURKC loss of function, with 4C chromosomal content [9]. The Maghreb founder variant, historically c.144delC, normalises under the 3' rule to NM_001015878.2:c.145del p.(Leu49TrpfsTer23) [51]. Globozoospermia (round heads without acrosomes) is mainly due to DPY19L2 deletions and variants, accounting for 66.7% of 54 fully analysed men and 84% of 31 in another series, and more rarely SPATA16, with a 22.6 kb founder deletion in Tunisians; the two genes explain up to 70% of globozoospermia, approximately 0.1% of male infertility causes [9]. ZMYND15 causes a spectrum from NOA with spermatid arrest to severe oligozoospermia with teratozoospermia, and a man labelled macrozoospermic and screened for AURKC actually had homozygous ZMYND15 loss of function [9]. SPINK2 was described in a French family with postmeiotic arrest, immotile pin-headed sperm and detached flagella [9]. Acephalic sperm are associated with SUN5 (definitive), PMFBP1 (strong) and TSGA10 (moderate), and fertilisation failure due to defective oocyte activation factor with PLCZ1 (definitive) [8].

2.8. Endocrine causes of central origin

Congenital hypogonadotrophic hypogonadism and Kallmann syndrome (hypogonadotrophic hypogonadism with anosmia) cause infertility through gonadotrophin-releasing hormone (GnRH) deficiency, with potentially normal spermatogenesis under stimulation [31, 39]. They are genetically heterogeneous, with over 20 genes and X-linked (ANOS1, formerly KAL1), autosomal dominant with incomplete penetrance (FGFR1, FGF8), autosomal recessive (PROKR2, PROK2, GNRHR) and frequently oligogenic inheritance; ANOS1 and FGFR1 explain approximately 15–25% of cases [2, 31, 39]. In females, OXF also lists HESX1, LHX3, PROP1, NR0B1 (X-linked congenital adrenal hypoplasia), NR5A1, leptin and its receptor and PCSK1 [4].

2.9. Genetics of premature ovarian insufficiency

Ovarian reserve forms before birth: after primordial germ cell migration, mitotic proliferation peaks around 20 gestational weeks, followed by atretic decline to approximately 1–2 million follicles at birth [40]. Genetic POI therefore results from three main mechanisms: formation of an insufficient reserve (gonadal dysgenesis), accelerated depletion of the formed reserve, or inability of follicles to respond to gonadotrophins [9, 40].

In Turner syndrome, X monosomy leads to gonadal dysgenesis with accelerated follicle loss; pregnancy is possible only when a 46,XX cell line is present or when a structural abnormality of the second X spares the Xq13–q26 region [35]. In a Danish series of 410 adult women with Turner syndrome (Birkebaek 2002), 49% had 45,X, 23% mosaicism with a structural abnormality of the second X, 19% 45,X/46,XX and 9% 46,XX with a structural abnormality of the second X; 31 had at least one spontaneous pregnancy, but only women with 45,X/46,XX or with a structurally abnormal X without a 45,X line had live births [35]. Age-related X loss makes low-level mosaicism difficult to interpret: the proportion of cells lacking one X rises from 1.5–2.5% in prepubertal children to approximately 4.5–5% above 75 years, and in one study the mean proportion of cells with a single X was 5.50% in women with POI versus 2.42% in age-matched controls [40, 45].

The FMR1 premutation (55–200 CGG repeats in the 5' untranslated region; MANE transcript NM_002024.6) is the most frequent monogenic cause of POI [26, 51]. Unlike the full mutation, which silences the gene through hypermethylation, the premutation increases FMR1 messenger RNA and reduces FMRP, with RNA toxicity [26]. Approximately 20% of premutation carriers have FXPOI, versus 1% of the general population, and the relationship with repeat size is non-linear: in Sherman's series (2005), the OR was 6.9 for 59–79 repeats, 25.1 for 80–99 and 16.4 above 100, with maximal risk between 80 and 100 repeats [26, 27]. Intermediate alleles (45–54 repeats) and high-normal alleles have shown no association with POI, and the full mutation neither increases FXPOI risk nor reduces ovarian reserve; results on the effect of AGG interruptions on FXPOI are conflicting [27]. FXPOI is X-linked; the Orphanet entry ORPHA:642691 assigns it autosomal recessive inheritance, which is incompatible with the location of FMR1 on the X [17, 26]. Sources differ on the proportion of POI explained by the premutation: approximately 3.2% of isolated and 11% of familial POI according to GeneReviews (Fink 2018), versus approximately 2% and 14% in the 2017 OXF [27, 40]. FMR1 genetics is common to fragile X syndrome and the premutation-associated disorders.

Table sources: [9–12, 25, 40].

The MCM8–MCM9 complex forms a hexameric helicase participating in replication, meiotic homologous recombination and mismatch repair, recruiting BRCA1 and RAD51; MCM8 lies at 20p12.3 and MCM9 at 6q22.31 [25]. Variants cluster in the N-terminal DNA-binding domain (55% in MCM8, 20% in MCM9) and AAA+ core (45% and 60%), gonadal dysfunction penetrance appears nearly complete (with two unaffected biallelic siblings without long follow-up), and no large intragenic deletions or duplications have been described [25]. Loss-of-function allele frequency in gnomAD v2.1.1 is approximately 1.4/100 000 for MCM8 and 2.5/100 000 for MCM9, and modelling estimates that approximately 0.02% of the population has biallelic pathogenic variants [25].

FSHR exemplifies founder effects: c.566C>T p.(Ala189Val) (NM_000145.4) accounts for 98% of pathogenic FSHR variants in Finns, with approximately 1 carrier in 85 in northern Finland; in 4981 screened samples, allele frequency was 0.96% in 1976 Finns, enriched in the northeast, 1/1162 in Swiss individuals and 0 in 1094 Danes and 540 Singaporean Chinese individuals [9, 51]. The clinical distinction is follicle presence: in a Finnish series, transvaginal ultrasound showed follicles in 6 of 8 women with FSHR variants versus 1 of 11 with other dysgeneses, and histology in 9 of 9 versus 1 of 4 [9]. Biallelic 46,XY individuals have variably impaired spermatogenesis without DSD [9].

The BMP15 inheritance model was corrected over two decades. The first report described sisters heterozygous for p.(Tyr235Cys), inherited from an unaffected father; later studies demonstrated null homozygosity in girls with primary amenorrhoea whose heterozygous mothers had normal menopause, compound heterozygosity for two frameshift variants in sisters, and p.(Cys320Tyr) homozygosity [9]. In a cohort of 500 women with POI or diminished reserve, 10.8% (54/500) had a BMP15 variant, but most were benign or uncertain and only one was homozygous loss of function [9]. Similarly, in 810 POI patients compared with ancestry-matched population data, 25% had at least one NOBOX variant; p.(Arg44Leu) was classified as benign, p.(Asp452Asn) and p.(Arg117Trp) as moderate-risk alleles with very low penetrance, and only p.(Gly91Trp) and p.(Gly152Arg) as pathogenic [9]. These examples explain why a POI panel frequently generates non-diagnostic monoallelic variants.

A meta-analysis of 11 studies with 1740 women with spontaneous POI estimated an exome monogenic P/LP variant rate of 31% (95% CI 18–44%) and, under strict criteria (excluding monoallelic variants in recessive genes and genes without a clear relationship), a diagnostic yield of 21% (95% CI 12–31%), with high heterogeneity (I² 87–89%) [54]. In an Estonian study of 51 women with unexplained POI, an “all-in-one” exome assessing variants in 288 candidate genes and CNVs above 0.5 Mb gave a conservative yield of 12% (6/51): three monogenic diagnoses (including TP63 p.(Arg97Gly) in three sisters and NR5A1 p.(Gly328Arg)) and three pathogenic CNVs (15q25.2 microdeletion including CPEB1 and BNC1 in two unrelated women, and an approximately 8.5 Mb Xq27.3–Xq28 microdeletion including FMR1) [55]. The source specifies no transcripts for these variants, presented here only at protein level.

2.10. Oocyte, fertilisation and maternal-effect defects

One group of genes causes female infertility with normal cycles and hormones, revealed only during in vitro fertilisation (IVF). PATL2 (autosomal recessive) causes oocyte arrest at germinal vesicle or metaphase I; in a series of 6 women with 10 biallelic variants, no pregnancy occurred in 16 cycles [9]. TUBB8 causes metaphase I arrest with an abnormal or absent spindle and fertilisation failure or embryonic arrest; Feng and colleagues (2016) described 7 families with dominant variants inherited from the father in 5 and de novo in 2, with fertile carrier fathers; recessive forms also exist, and in a systematic review of 35 women with TUBB8, KIF11 or CKAP5 variants, no viable pregnancy occurred with their own oocytes in the presence of a pathogenic TUBB8 variant [9]. Recessive ZP1 variants give rise to cumulus–oocyte complexes without a normal oocyte or to oocytes lacking the zona pellucida (genuine empty follicle syndrome), ZP2 variants to a thin zona unable to bind sperm, which can be overcome by ICSI, and the dominant-negative ZP3 variant c.400G>A p.(Ala134Thr) (NM_001110354.2) to recurrent empty follicle syndrome [9, 11, 51]. Orphanet estimates female infertility due to zona pellucida defects at fewer than 1/1,000,000, with 4 cases at the time of assessment [21]. WEE2 (autosomal recessive) prevents exit from metaphase II; in a 2026 meta-analysis of 105 studies, pooled total fertilisation failure was 66% (95% CI 44–82%) and the fertilisation rate 3%, versus 9% and 67% in women without an identified oocyte mutation [9]. PADI6 is a maternal-effect gene: a woman with biallelic variants is healthy but has recurrent early embryonic arrest, pregnancy losses and hydatidiform mole, and children who are born may have multilocus imprinting disturbance, such as Beckwith–Wiedemann or Silver–Russell syndromes; NLRP5, NLRP2, NLRP7 and KHDC3L belong to the same group [9].

2.11. Recurrent variants and normalisation

Table sources: [9, 11, 28, 51]. ERAL1 and LARS2 variants are reproduced with the GeneReviews transcript, without MANE normalisation. The genomic 5T description returned by VariantValidator does not match the transcript description, and repeat description is annotation only [51].

3. Clinical Spectrum and Manifestations by System

3.1. The infertile male: semen and testicular phenotypes

Almost 90% of infertile men have at least one altered semen parameter — count, motility or morphology [39]. Most genetic spermatogenic failure causes have no extragonadal manifestations: AZF deletion carriers are generally healthy asymptomatic men, with normal physical examination in approximately 30% and small testes in approximately 70%, corresponding to SCO [2]. The GeneReviews count classification (azoospermia; severe oligozoospermia <1 million/mL; moderate 1–5 million/mL; mild 5–20 million/mL) is useful for genetic reasoning because, except for gr/gr, AZF deletion carriers never have concentrations above 2 million/mL, and above 5 million/mL count–pregnancy correlation is weak [2]. AZF deletions have never been described in normozoospermic men, causing azoospermia or oligozoospermia rather than “infertility” broadly [34]. Testicular biopsy, when performed, shows SCO, maturation arrest (spermatocytes without spermatids) or hypospermatogenesis, and in approximately 60% of men with NOA in each histological group, spermatogenic foci with some sperm are found, according to GeneReviews authors [2]. NOA is accompanied by hypogonadism in approximately 30% and may be the first sign of a pituitary or germ cell tumour [3].

Male infertility is associated with greater mortality, neoplasia and other disease, leading AUA/ASRM to describe it as a possible “canary in the coal mine” of male health, and EAU to report greater long-term cardiometabolic disease, cancer and mortality risk in men with NOA [3, 6]. Some monogenic causes imply specific comorbidities: identifying DNAI1 in an infertile man led to primary ciliary dyskinesia diagnosis and CFTR to mild CF in a Dutch clinical exome series [7]. A seven-step Radboud protocol (Netherlands), published in May 2026, proposes gene-specific phenotyping based on tissue expression profiles and literature to detect monogenic cause-associated comorbidities; applied to two men (MEI1, with extensive immune profiling, and DNAH17, with retinal functional assessment and imaging), it found no clinically relevant abnormalities at assessment [56].

3.2. Klinefelter syndrome: reproductive aspects

The phenotype ranges from the normally virilised man to the man with stigmata of androgen deficiency; infertility, with reduced testicular volume, is often the only complaint, and neuropsychological, learning and language difficulties are frequent [3]. Other manifestations include testosterone deficiency, reduced muscle mass, less body hair, gynaecomastia, autoimmune diseases and osteoporosis, and the 2021 EAA guideline adds a higher prevalence of cardiovascular, metabolic, bone, dental, coagulation and autoimmune disease [6, 44]. Most patients are diagnosed in adulthood and a substantial fraction is never diagnosed; a Brazilian source estimates that 66% never reach a diagnosis [32, 33, 44]. Men with non-mosaic Klinefelter syndrome rarely have sperm in the ejaculate, and unaided paternity is rare; exceptional spontaneous fertility is attributed to cryptic 47,XXY/46,XY mosaicism [6, 32]. Surgical retrieval is discussed in 7.3.

3.3. Y microdeletions: genotype–phenotype correlation

Table sources: [2, 3, 6, 34].

Differences in AZFc retrieval estimates illustrate data origin effects: the 87% GeneReviews rate comes from one author and centre, whereas the approximately 50% mean derives from 32 studies; EAU reports 50–75% and AUA/ASRM approximately 50% by micro-TESE (microsurgical testicular sperm extraction) [2, 3, 6, 34]. A peripheral blood 45,X line above 5% negatively predicts spermatogenesis [34]. Declining counts over time have been reported in AZFc carriers, but a study of 4 patients followed for 14 months to 7 years showed no difference [34]. Classical complete deletions confer neither cryptorchidism nor testicular cancer risk, unlike gr/gr [3, 34]. Complex Y rearrangements may be associated with short stature through loss of SHOX or a putative pericentromeric gene (GCY) [2].

3.4. 46,XX male and 45,X/46,XY mosaicism

Approximately 85% of 46,XX men present after puberty, with normal pubic hair and penis, small testes, gynaecomastia and azoospermia; approximately 15% are recognised at birth through ambiguous genitalia [30]. Histology shows complete SCO with atrophy and hyalinisation, testosterone is low and oestrogen and gonadotrophins elevated; gender identity is male and untreated testosterone deficiency develops [6, 30]. Adult male 45,X/46,XY mosaicism may remain unnoticed until infertility investigation, with short stature, dysgenetic testes and Turner features, as in section 10's case [45, 57].

3.5. Obstructive azoospermia of genetic origin

Men with CBAVD have ejaculate volume below 1.0 mL and pH below 7.0, due to absent seminal vesicles or vasa deferentia, with normal testicular volume and FSH [3]. CBAVD accounts for approximately 1% of infertile men and up to 6% with OA, and CAVD of all causes for approximately 0.1% of men [3, 9]. History should seek respiratory symptoms, nasal polyps, chronic sinusitis and pancreatic insufficiency [39]. CUAVD is usually associated with ipsilateral renal agenesis and probably has another genetic cause; renal abnormalities are rare when CBAVD is due to CFTR [3]. Young syndrome (sinusitis and infertility) has unknown inheritance and prevalence according to Orphanet [58].

3.6. Qualitative sperm defects

Men with DNAH1-related MMAF are otherwise healthy; assessment should include questions about respiratory symptoms and laterality abnormalities [9]. In primary ciliary dyskinesia, male subfertility is common, semen analysis shows normal or reduced counts and immotile or very poorly motile sperm, and approximately 50% have laterality defects; female fertility may be reduced by oviduct ciliary dysfunction, with greater concern regarding ectopic pregnancy [29, 39]. In AURKC-related macrozoospermia, approximately 100% of sperm are abnormal, and homozygous women are fertile [9]. Syndromic infertility phenotypes include deafness–infertility syndrome (CATSPER2), polycystic kidney disease with asthenozoospermia (PKD1) and occult Fanconi anaemia (FANCA) [8].

3.7. MCM8/MCM9 syndromes

The 2026 GeneReviews compiles 54 published individuals (26 MCM8, 28 MCM9), with fertility-study ascertainment bias and few males [25].

Table source: [25] (Helderman 2025 data).

Gonadal dysfunction occurs in 88% (23/26) of MCM8 patients and 93% (26/28) of MCM9, typically recognised between 10 and 30 years, proportions possibly inflated by ascertainment [25]. Females have primary or secondary amenorrhoea, an underdeveloped uterus, small or streak ovaries and absent, delayed or incomplete puberty; males have NOA, severe oligoasthenozoospermia or SCO, with fluctuating semen parameters — sperm presence, even normal on one assessment, does not exclude diagnosis [25]. Germ cell tumours (yolk sac tumours, dysgerminomas, gonadal tumours with marked dysgenesis) occurred only in females, between 11 and 15 years [25]. In biallelic MCM9 carriers, CRC was diagnosed between 30 and 60 years and polyps between 19 and 68 years, with gastric cancer enrichment (OR 27.03; 95% CI 2.93–248.5); in the 100,000 Genomes Project, 51 biallelic MCM8 individuals had no CRC or polyposis enrichment [25]. Heterozygotes may have reduced fertility — hypogonadism in 29% (14/49) of MCM8 heterozygotes and 22% (10/45) of MCM9 — without clear evidence of increased cancer risk [25].

3.8. The infertile female: primary amenorrhoea and POI

The four most common primary amenorrhoea causes in an OXF-cited series (Timmreck and Reindollar 2003) were gonadal dysgenesis (48.5%), congenital absence of uterus and vagina (Mayer–Rokitansky–Küster–Hauser syndrome, MRKH; 16.2%), GnRH deficiency (8.3%) and constitutional pubertal delay (6.0%) [4]. In established POI, menopause typically precedes menarche in Turner women, some of whom menstruate briefly [40]. More than one-third of Turner girls develop pubertal signs (twice as frequently in non-45,X), only 1 in 5 has spontaneous menarche and spontaneous pregnancy occurs in approximately 10%, mainly mosaics [43].

FXPOI may begin from 11 years, with primary amenorrhoea and delayed puberty, but generally presents as oligomenorrhoea and secondary amenorrhoea with hypergonadotrophic hypogonadism; ovarian function is erratic, some women maintain irregular ovulation for years and up to 12.6% conceive after diagnosis [27]. Sequelae include osteoporosis, cardiovascular disease and greater thyroid disease risk; fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in approximately 16% of women and 40% of men with premutations [26, 27].

In BPES, all FOXL2 variant carriers have eyelid malformation (blepharophimosis, ptosis, epicanthus inversus, telecanthus), and females have age-dependent POI with reduced penetrance; secondary sexual characteristics are usually normal, most have normal menarche followed by oligomenorrhoea and secondary amenorrhoea, and some have hypopituitarism [12]. In Perrault syndrome, bilateral sensorineural deafness ranges from profound congenital, detectable on neonatal hearing screening, to moderate childhood-onset, with a downsloping 4–8 kHz audiogram and cochlear nerve hypoplasia in up to 10%; ovarian dysfunction ranges from dysgenesis with streak gonads and primary amenorrhoea to POI, and type 2 adds developmental delay, ataxia, neuropathy and sometimes metabolic crisis with elevated lactate [11]. Perrault males generally have normal fertility, but azoospermia and undervirilisation have been described [11]. Classical galactosaemia is associated with POI particularly with homozygous p.(Gln188Arg) and mean treated erythrocyte galactose-1-phosphate above 3.5 mg/dL [40]. Autoimmune polyglandular syndrome type 1 (AIRE) combines hypoparathyroidism, adrenal insufficiency, type 1 diabetes, thyroid disease and hypogonadism [40]. Trisomy X (47,XXX) has normal puberty and probably normal fertility, but POI is more prevalent than in controls; in tetrasomy X (48,XXXX), menstrual disorders are common and fertility reduced [59].

In MRKH syndrome, women are 46,XX, with normal ovaries and female sexual characteristics but no uterus, cervix or upper two-thirds of the vagina; aetiology is largely unknown and heterogeneous, with 16p11.2 and 17q12 microdeletions in 4 of 38 (10.5%) isolated Müllerian aplasia cases and 16p11.2, 17q12 or distal 22q11.2 in 5 of 25 (20%) syndromic cases [4]. Renal abnormalities (unilateral agenesis, ectopia) occur in approximately 30% and skeletal abnormalities in 11–12% [4]. HNF1B variants (cystic renal disease and diabetes, MODY5) cause genital tract defects in approximately 20% of women (bicornuate uterus, vaginal aplasia, rudimentary uterus) [4]. Non-classical congenital adrenal hyperplasia (CAH) may present with adult subfertility, and complete androgen insensitivity syndrome (CAIS; 46,XY, AR) with primary amenorrhoea, absent uterus and sparse hair [4].

Oocyte defects (PATL2, TUBB8, ZP1–ZP3, WEE2) have no manifestation outside the IVF cycle: women have normal cycles and hormones, and phenotype emerges only as oocyte arrest, empty follicles, absent zona pellucida or total fertilisation failure [9].

4. Clinical Recognition and Warning Signs

A genetic cause should be suspected in any man with azoospermia or severe oligozoospermia, any woman with non-iatrogenic POI and whenever infertility accompanies extragonadal manifestations, family history or repeated specific ART failures. History includes a three-generation pedigree covering pregnancy losses, stillbirths, intellectual disability, congenital abnormalities, familial infertility, female relatives' menopausal age and Down syndrome cases [39, 40, 46]. Male examination should assess secondary sexual characteristics, testicular volume and consistency and vas deferens presence; female examination, height, Turner signs, secondary sexual characteristics and pelvic examination [4, 39, 40].

Table sources: [2, 3, 5, 6, 9, 11, 12, 25, 29, 31, 34, 46].

In children and adolescents, signs prompting early diagnosis are delayed or incomplete puberty, primary amenorrhoea, testes small for pubertal stage and short stature; suspicion of a genetic POI cause should begin with the first signs because follicular reserve may be exhausted before any preservation opportunity [5, 12]. Men with NOA should be informed that their condition is probably genetic (Y deletion, translocation or Klinefelter) before testicular sperm extraction (TESE) followed by ICSI [2]. Relatively urgent signs are rare but exist: a testicular mass or microcalcifications in a man with dysgenetic gonads, pituitary tumour signs, an adnexal mass in a girl with MCM8/MCM9 or gonadal dysgenesis with Y material, and pregnancy wishes in a Turner woman without prior cardiovascular assessment [3, 25, 43]. No neonatal screening targets genetic infertility causes; neonatal hearing screening may identify Perrault congenital deafness [11].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Initial male assessment

Investigation begins with WHO-standard semen analysis, confirming azoospermia twice (strong EAU recommendation) and examining the post-centrifugation pellet to exclude cryptozoospermia [3]. Lower 2010 WHO reference values reproduced in OXF were volume ≥1.5 mL, pH ≥7.2, concentration ≥15 million/mL, total count ≥39 million per ejaculate, total motility ≥40% or progressive ≥32%, vitality ≥58% and normal morphology ≥4% [39]. Initial azoospermic male assessment includes, according to AUA/ASRM, physical examination, semen volume and pH and FSH; diagnostic testicular biopsy should not routinely distinguish OA from NOA [6]. EAU characterises OA by at least one testis above 15 mL, dilated epididymis or absent vas deferens, with normal FSH and inhibin B [3]. Hormonal investigation (testosterone, FSH, LH, prolactin and thyroid function) guides hypergonadotrophic or hypogonadotrophic hypogonadism diagnosis [39]. FSH correlates negatively with spermatogonial numbers, but FSH and testicular volume may be normal in maturation arrest, and FSH does not accurately predict TESE outcome; lower preoperative serum AMH was associated with greater micro-TESE retrieval in as yet unconfirmed data [3].

5.2. Genetic testing indications according to guidelines

Table sources: [3, 5, 6, 34].

Divergences have practical consequences. EAU formally recommends karyotyping and genetic counselling for all men with azoospermia or oligozoospermia below 5 million/mL, but its own text considers karyotyping “currently indicated” below 10 million/mL, retaining this threshold pending cost-effectiveness studies; the graded recommendation is 5 million/mL [3]. AUA/ASRM adds clinical criteria (elevated FSH, testicular atrophy or diagnosed impaired sperm production) to the concentration threshold, reducing test numbers but potentially leaving men with maturation arrest, normal FSH and normal testicular volume without a karyotype, although abnormalities also occur in them [3, 6]. For Y testing, AUA/ASRM lowered the threshold in 2024 from ≤5 to ≤1 million/mL, based on a meta-analysis of North American and European studies where deletions occurred in 5% of men with 0–1 million/mL and only 0.8% above 1 to 5 million/mL; EAU makes testing mandatory below 1 million/mL and discretionary up to 5 million/mL, and EAA/EMQN recognises questionable cost-effectiveness above 1 million/mL [3, 6, 34]. EAA/EMQN emphasises that clinical parameters (hormones, testicular volume, varicocele, cryptorchidism, infections) do not predict deletion presence and a “non-idiopathic” diagnosis (testicular tumour, epididymal occlusion, orchitis, varicocele, after chemotherapy or radiotherapy) with azoospermia or severe oligozoospermia remains an indication, with testing before varicocelectomy [34]. EAU considers genetic counselling mandatory before ART in men with NOA (strong) [3].

5.3. Karyotype

G-banded karyotyping detects aneuploidies, translocations, inversions and Y rearrangements but has approximately 5–10 Mb resolution [47]. A 30-cell count is recommended for sex chromosome mosaicism, and EAA/EMQN recommends an extended 100-metaphase karyotype in complete AZFc or terminal Yq deletion to exclude 46,XY/45,X mosaicism with a structurally abnormal Y [34, 40]. Standard karyotyping, extended to 30 cells only when at least one abnormal cell is found, may miss mosaicism below 20% [7]. Karyotyping is irreplaceable for balanced translocations: microarray and exome do not detect them, and Robertsonian translocations, approximately 40% of balanced translocations in infertile men at one Dutch laboratory, are undetectable by short- or long-read sequencing or optical mapping [7, 47]. In a 46,XX male, karyotyping should be complemented by SRY FISH or CMA and, if negative, CNV analysis around SOX3 and SOX9 [30]. Sex chromatin (Barr bodies) is no longer used for Klinefelter diagnosis because of false negatives [33].

5.4. Y microdeletions

The reference method is two-step multiplex PCR of sequence-tagged sites (STSs) [34]. Basic testing uses two STSs per region — AZFa sY84 (with updated reverse primer) and sY86; AZFb sY127 and sY134; AZFc sY254 and sY255 (amplifying all four DAZ loci) — with internal controls (SRY, through sY14, and ZFX/ZFY), a male positive control with normal spermatogenesis, female negative control and water blank [34]. When a deletion is found, extension analysis is mandatory: for AZFa, sY82 (present) and sY1064 (absent) proximally and sY1065 or sY1182 (absent) and sY88 (present) distally; for AZFb, sY105 (present) and sY121 or, if present, sY1224 (absent) proximally, and sY1192 (absent) and sY153 (present) distally; for AZFc, sY160, whose presence indicates b2/b4 deletion and absence terminal deletion; and in AZFbc, sY116, present in P4/distal P1 and absent in P5/distal P1 [34]. This protocol detects virtually all clinically relevant deletions and over 95% of those described [3, 34].

The 2023 changes corrected specific problems: proximal AZFa markers sY83 and sY1064 are not interchangeable because complete AZFa deletions may retain sY83; distal AZFb markers sY143 and sY1192 likewise are not, and only sY1192 distinguishes complete from partial AZFb deletion, directly affecting TESE prognosis; the sY84 reverse primer was updated because of a single-nucleotide polymorphism (rs72609647) in Asian populations; and AZFb breakpoint variability may retain sY1224 [34]. No commercial kit available at the time was fully compatible with these changes, and excess-marker kits produce false deletions; multilocus markers sY114 and sY152 should be avoided, the “AZFd region” does not exist, and an isolated sY254 or sY255 deletion represents technical error [34]. gr/gr testing is discretionary for laboratory and clinician, with absent sY1291 and present sY1191, and a multicentre study found 5% false deletions [34]. Partial deletions are difficult to interpret, without standardisation, and kits with few primers may miss them [6]. GeneReviews states that CMA detects AZF deletions but multicopy genes complicate interpretation, and USP9Y sequencing does not detect exon deletions [2]. Alternative approaches — capillary electrophoresis, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridisation (aCGH) and NGS — require validation, and NGS particularly requires considerable experience because of ampliconic structure; exome reliably detects only single-nucleotide variants and CNVs in single-copy AZF genes (USP9Y, DDX3Y, KDM5D, EIF1AY, RPS4Y2) [7, 34].

The report should present an STS table with “present” or “absent” (not “+” or “−”), method, limitations, kit name and version and two signatures; in complete AZFa, AZFb and AZFabc deletions, incompatible with sperm production, family screening is not indicated and should not be mentioned, whereas complete AZFc and partial AZFa or AZFb reports should request male relative testing [34]. The EAA/EMQN external quality assessment scheme (2000–2022) expanded from 57 to 148 laboratories between 2000 and 2012, and genotyping error fell from nearly 8% to 1–2%; performance declines in 2006 and 2012 involved 46,XX male cases, in whom testicular sperm cannot be obtained [34].

5.5. CFTR testing and absent vas deferens

CFTR testing should be performed in any patient with unilateral or bilateral absent vas deferens or seminal vesicle agenesis, and in CUAVD with normal kidneys [3]. AUA/ASRM recommends CFTR carrier testing, including 5T allele assessment, in men with vas deferens agenesis or idiopathic OA [6]. Because OA-causing variants may differ from CF-causing variants, AUA/ASRM suggests considering expanded carrier screening or full-gene sequencing rather than limited variant panels [6]. EAU describes approximately 2000 variants and AUA/ASRM over 1500, and the most frequent (F508del, R117H, W1282X) vary by ethnicity [3, 6]. With absent vas deferens without CFTR variants, abdominal ultrasound should be performed and may reveal abnormalities from absent to pelvic kidney; OXF recommended renal ultrasound in azoospermic men with normal karyotypes in the CBAVD setting [3, 39]. With normal kidneys and negative or monoallelic CFTR testing, ADGRG2 is next, by panel or exome [9, 60]. Within CF diagnostic criteria, CBAVD belongs to group 1 phenotypic characteristics, and CFTR-RD confirmation requires careful exclusion of non-classical CF [28, 39, 50].

5.6. Exome and multigene panels in male infertility

Table sources: [7, 52, 53, 60].

The Radboud “all-in-one” exome was validated in 17 AZF deletions, 37 sex chromosome aneuploidies or structural abnormalities, 26 CFTR cases and 90 controls, detecting all previously known variants and showing 100% concordance for non-mosaic sex chromosome abnormalities (47,XXY, 47,XYY, 46,XX SRY+, idic(Y), iso(Y)) [7]. In the clinical series, 17 patients (5.8%) had chromosomal abnormalities, all also karyotyped; 6 (2.1%) complete AZF deletions (one AZFb P5/proximal P1 and five AZFc b2/b4); 10 (3.4%) a monogenic cause (four MMAF due to CFAP43, CFAP69, DNAI1 and FSIP2; azoospermia due to heterozygous NR5A1 and another X-linked gene; two DPY19L2 globozoospermia cases, including a homozygous deletion); 9 (3.1%) were CF carriers; and 12 (4.1%) had variants of uncertain significance (VUS) requiring segregation or RNA investigation [7]. Gene analysis added 6.8% (20/292), and 79.8% remained unexplained, with future reanalysis possible [7]. Zhou and colleagues' meta-analysis identified 270 positive cases with variants in 262 genes, most frequently AR, TEX11, FANCM, TDRD9, PNLDC1, M1AP, FBXO15 and DMRT1; among positive cases with TESE data, only 5 of 45 (11.11%) had successful retrieval, and the authors acknowledge the 15% estimate may overestimate yield in general NOA populations because of heterogeneity and consanguinity in some cohorts [53].

Exome as a first-line test is debated. Schlegel, commenting in February 2026 on a 45,X/46,XY mosaicism case, argued that karyotyping and Y microdeletion testing are “necessary and sufficient” for NOA management decisions, standard karyotyping almost always reflects clinically relevant mosaicism and exome in all NOA men is unnecessary when following AUA/ASRM guidance [61]. In response, Tjagur and colleagues clarified that they advocate exome not in all men with NOA but as first line in severe spermatogenic failure with suspected genetic cause, because standard tests diagnose 15–20% of NOA, exome diagnosed over 10% of idiopathic cases with suspected monogenic origin at their centre, detects mosaicism, permits reanalysis and costs no more than current tests combined [62]. The Radboud team estimated exome plus karyotype costs as similar (difference below 10%) to AZF, common CFTR panel and karyotype, with turnaround of 4–6 versus 8–12 weeks sequentially [7]. At this review date, no guideline formally recommends routine exome in male infertility: EAU requires validation in geographically and ethnically diverse cohorts before recommending it and considers MTHFR and XRCC1 polymorphisms susceptibility factors without clinical utility [3].

5.7. POI diagnosis and female genetic investigation

The 2024 criteria are menstrual disturbance (amenorrhoea or irregular cycles) for at least 4 months and FSH above 25 IU/L; one elevated measurement suffices (the 2015 guideline required two), FSH may be sampled on any cycle day and is repeated after 4–6 weeks only if diagnosis is uncertain [5]. Hormonal contraception may mask or cause amenorrhoea and lower FSH; bilateral salpingo-oophorectomy before 40 years equates to POI without further tests; diagnosis is not based on oestradiol, and AMH is neither a primary diagnostic test (it may confirm when FSH is inconclusive) nor suitable for predicting POI [5]. Older criteria still cited in FMR1 GeneReviews (4–6 months' amenorrhoea and two menopausal-range FSH values at least one month apart) and BPES GeneReviews (FSH above 25 IU/L twice at least 4 weeks apart, oestradiol below 50 pg/mL) were superseded by 2024 criteria [5, 12, 27].

The guideline recommends karyotype and FMR1 premutation testing in all women with non-iatrogenic POI (strong recommendations, low certainty) and allows additional testing such as NGS where available and after comprehensive genetic counselling (conditional) [5]. Age should not restrict testing access, implications should be discussed before sampling and women should be informed that the cause may remain unidentified [5]. FMR1 requires specific testing because multigene panels and NGS do not detect premutation [5]. The 2021 ACMG standard classifies alleles as normal (5–44 repeats), intermediate or “grey zone” (45–54), premutation (55–200) and full mutation (over 200, with promoter hypermethylation); PCR measuring the region to 200 repeats has >99% sensitivity for fragile X syndrome, but more than one method is often necessary (triplet repeat-primed PCR, Southern blot for methylation and mosaicism), and in women two differently sized normal alleles must be distinguished from a normal allele plus premutation; reports should state allele size, not category alone [26]. AGG interruptions (every 9–10 repeats in stable alleles) reduce expansion risk and are relevant to counselling [26]. ACMG, the American College of Obstetricians and Gynecologists (ACOG) and National Society of Genetic Counselors (NSGC) recommend FMR1 testing in ovarian insufficiency before 40 years [26].

In unexplained POI, the guideline recommends anti-21-hydroxylase antibodies (strong, very low certainty), with endocrinology referral if positive; anti-ovarian antibodies are unsuitable for diagnosis; TSH should be measured at diagnosis and every 5 years or with symptoms, without routine anti-peroxidase testing [5]. Classical hormonal amenorrhoea investigation includes FSH, LH, prolactin and thyroid function, pelvic ultrasound or magnetic resonance imaging (MRI) and ovarian and adrenal androgen measurement [4]. Suspected 17α-hydroxylase-deficient CAH requires 11-deoxycorticosterone and androstenedione measurement [11]. OXF already advised considering array, exome or genome with suspected monogenic disease, a malformation syndrome or strong family history [4].

POI exome studies show higher yields in primary amenorrhoea. In the Chinese study of 1030 women, yield was 25.8% in primary amenorrhoea (biallelic 5.8%) versus 17.8% in secondary (biallelic 1.9%), and FSHR explained 4.2% of primary versus 0.2% of secondary amenorrhoea [10]. In the Estonian study, yield was 5/9 (56%) in primary versus 1/42 (2%) in secondary amenorrhoea or oligomenorrhoea [55]. In the 2026 meta-analysis, strict yield was 33% (95% CI 16–49%) in primary and 18% (5–32%) in secondary amenorrhoea [54].

5.8. Test limitations

Table sources: [2, 3, 5–7, 12, 26, 30, 34, 47].

A negative result does not exclude a genetic cause. In FOXL2, a significant fraction of coding variants are polyalanine expansions potentially escaping standard targeted sequencing, and extragenic regulatory variants require genome, targeted MLPA, array, optical mapping or long-read sequencing [12]. In MCM8 and MCM9, sequencing detects 100% of described variants because no large intragenic deletions or duplications have been reported, but biallelic uncertain variants neither establish nor exclude diagnosis [25]. The proportion of variants detectable by a method does not equate to clinical sensitivity for an entity: in Y testing, “over 90%” refers to AZF deletions identified by each method, not the proportion of men with explained spermatogenic failure [2].

5.9. Reporting, variants of uncertain significance and segregation

A molecular test report should identify gene, versioned reference transcript, Human Genome Variation Society (HGVS) description, zygosity and pathogenicity class under ACMG and Association for Molecular Pathology (ACMG/AMP) criteria; in Münster, classification followed ACMG and ClinGen guidelines, with one transcript per gene [60]. VUS require family segregation or RNA studies before any decision [7]. In recessive genes, a single pathogenic variant is non-diagnostic, and in genes such as BMP15 and NOBOX, monoallelic missense variants should be interpreted as low-penetrance risk factors or uncertain findings [9, 10]. In X-linked genes (TEX11, ADGRG2), segregation with the mother and maternal male relatives assists classification [9]. Variants identified in the Estonian POI study were submitted to ClinVar and ESHRE's reproductive genetics special interest group's FeRGI database, illustrating data sharing improving future classification [55].

5.10. Practical algorithm

Table sources: [3, 5, 6, 9, 34, 39, 40].

5.11. Prenatal and preimplantation diagnosis

When the genetic cause is known, prenatal diagnosis and PGT options depend on mechanism. In ART pregnancies using sperm from a man with a Y deletion, fetal sex or deletion testing is possible, as is prenatal testing for 45,X risk associated with paternal Y rearrangements [2]. In translocation carriers, EAU recommends PGT for structural rearrangements (PGT-SR) or amniocentesis [3]. Technical details and residual risks are developed in section 8.

6. Differential Diagnosis

Genetic infertility differential diagnosis has two levels: distinguishing genetic causes from each other and from acquired causes, frequently coexisting. Most male infertility remains unexplained, and male factor involvement in approximately half of couples is poorly documented; oligozoospermia severe enough to cause infertility occurs in only approximately 10% of infertile couples [2]. Acquired or non-genetic causes include ejaculatory duct obstruction, antisperm antibodies (of controversial significance), infections (mumps orchitis, epididymitis, urethritis), varicocele (much-debated relevance), trauma, testicular tumours, radiation, chemotherapy or heat exposure and endocrinopathies such as hyperprolactinaemia [2]. In an EAU-cited single-centre series of 10,469 patients, a known or possible cause existed in 42.6%; among azoospermic men, cryptorchidism occurred in 17.2%, varicocele in 10.9%, testicular tumours in 2.8% and neoplasia-related cryopreservation in 12.5% [3].

Table sources: [2–5, 8, 9, 11–13, 25, 27, 29–31, 34, 39, 40, 45].

In azoospermia, the first distinction is OA versus NOA, determining retrieval technique and testing panel: ejaculate volume and pH, testicular volume, vas palpation and FSH separate most cases [3, 6]. Sertoli-cell-only syndrome is not specific to genetic causes: it may result from Y deletion, chemotherapy or radiotherapy, mumps orchitis, Down syndrome, Klinefelter, congenital adrenal hypoplasia, isolated FSH deficiency or hyperprolactinaemia [2]. Kallmann syndrome is distinguished by hypogonadotrophic hypogonadism, neonatal micropenis and cryptorchidism in some patients, incomplete secondary sexual characteristics and adult prepubertal testicular volume; non-reproductive phenotypes guide gene selection — synkinesis, unilateral renal agenesis, sensorineural deafness and high-arched palate with ANOS1; synkinesis, cleft lip or palate, tooth agenesis, brachydactyly or syndactyly and corpus callosum agenesis with FGFR1 [2]. A variant form, “fertile hypogonadotrophic hypogonadism”, combines low testosterone with partial pubertal development, near-normal testicular volume, normal inhibin B and sometimes ejaculated sperm [31].

In females, primary amenorrhoea with low oestrogen and elevated gonadotrophins requires first excluding Turner and other X abnormalities, because all Perrault women are 46,XX and 78% of adult Turner women also have progressive high-frequency sensorineural deafness [11]. Irregular cycles may reflect polycystic ovary syndrome, thyroid disease or hyperprolactinaemia, and non-genetic POI causes include autoimmunity and chemotherapy [27]. Childhood cancer survivors have high risk: in a Danish series of 100 survivors, approximately 1 in 6 developed POI and the remainder had diminished reserve [40]. Ovarioleukodystrophies (AARS2 and EIF2B-related vanishing white matter leukoencephalopathy) and a Perrault-like phenotype with CLDN14 and SGO2 homozygosity belong in the differential of POI with neurological signs or deafness [11, 27]. HROB (MCM8IP), SPIDR and genes underlying Fanconi anaemia, Bloom (BLM) and Werner (WRN) syndromes are MCM8/MCM9 differentials because they share DNA repair pathways [25]. Polyposis syndromes without gonadal dysfunction (APC, MUTYH, NTHL1, MSH3, Lynch syndrome, constitutional mismatch repair deficiency, POLE/POLD1, PTEN, STK11, SMAD4/BMPR1A, GREM1) are distinguished from MCM9 by absent gonadal insufficiency [25].

7. Treatments and Risk Management Strategies

7.1. General principles

No genetic infertility cause has approved targeted pharmacological treatment. Management rests on four pillars: obtaining usable patient gametes (surgical sperm retrieval, ICSI, oocyte activation, fertility preservation); replacing lost hormonal function without compromising residual fertility; using donor gametes, adoption or fostering when own-gamete probability is zero; and preventing transmission through PGT or prenatal diagnosis [3, 5, 36]. Genetic diagnosis therefore has prognostic value that should be used before invasive procedures: in complete AZFa or AZFb deletions, 46,XX males and several meiotic arrest genes, sperm retrieval probability is zero or very low and surgery should not be proposed [3, 9, 34]. Infertility management belongs to reproductive medicine, and the geneticist's role is to explain genetic basis and reproductive implications of using own gametes [39].

7.2. Surgical sperm retrieval in non-obstructive azoospermia

EAU considers micro-TESE the treatment of choice in NOA (weak recommendation) and AUA/ASRM the technique to use (moderate, grade C) [3, 6]. Per-cycle rate is independent of age and hormones and increases with testicular volume; hypospermatogenesis histology is the best predictor, and Klinefelter and previous cryptorchidism are associated with greater retrieval probability than other NOA causes [3]. Adverse effects include a mean total testosterone fall of 2.7 nmol/L 6 months after conventional TESE, recovering within 18–26 months, intratesticular haematoma in 51.7% at 3 months and fibrosis in up to 30% at 6 months after conventional TESE, leading EAU to consider long-term endocrine follow-up reasonable after any TESE [3]. Presurgical hormone therapy (human chorionic gonadotrophin [hCG], FSH, selective oestrogen receptor modulators [SERMs] or aromatase inhibitors) has shown no benefit in randomised idiopathic NOA trials and is not routinely recommended by EAU; AUA/ASRM considers data limited (conditional) [3, 6]. Varicocelectomy is not indicated in azoospermic men and has no definitive evidence before NOA retrieval [6].

7.3. Male management by entity

Klinefelter syndrome. TESE or micro-TESE retrieves sperm in up to 50% of men according to the EAU and in 50–60% of 47,XXY men by micro-TESE according to the AUA/ASRM [3, 6]. The meta-analysis by Momtazi-Mar and colleagues (2025), with 48 studies and 2815 men with non-mosaic Klinefelter syndrome, estimated a median retrieval rate of 44% and a median live birth rate of 11.1% (22 studies); groups with successful retrieval were, on average, 2.8 years younger (95% CI −3.62 to −2.02; I² 78%), but there was no difference between adolescents under 20 years and adults (45% vs 42%), with a non-significant suggestion of decline after 40 years, and the authors concluded that retrieval may safely be deferred to adulthood [63]. In the series of Greco and colleagues (2013), in 38 azoospermic men with non-mosaic Klinefelter syndrome, sperm was retrieved in 15 (approximately 40%), with 26 ICSI cycles, 15 pregnancies and 16 babies [32]. The EAU considers peri- or prepubertal TESE for spermatogonial cryopreservation experimental, only in a research setting, and notes some evidence of greater retrieval at younger ages without a defined age threshold [3]. The 2017 OXF suggested a possible pubertal window for fertility preservation, a position not supported by the 2025 meta-analysis [32, 63]. Testosterone may be considered for hypogonadism once fertility issues have been resolved, because exogenous testosterone suppresses spermatogenesis, and testosterone initiation is associated with greater metabolic and cardiovascular risk, including venous thromboembolism [3, 6].

AZF microdeletions. Deletion screening should be offered to all azoospermic men eligible for TESE-ICSI [34]. In complete AZFa and AZFb deletions, including AZFbc and AZFabc, TESE is not indicated (strong EAU recommendation), because no complete AZFa success has been recorded and probability is virtually zero in complete AZFb; surgery may be attempted in atypical AZFb with a proximal P4 breakpoint and partial deletions with sY1192 present [3, 34]. In complete AZFc, retrieval is approximately 50% [6, 34]. A 12-study meta-analysis showed only fertilisation rate is significantly lower with ICSI in complete AZFc; embryo quality, clinical pregnancy, miscarriage and live birth are equivalent to couples without genetic abnormalities, using ejaculated or testicular sperm [34]. In AZFc men with oligozoospermia, ejaculated sperm should be cryopreserved, and GeneReviews warns that hormones or nutritional supplements could worsen severe oligozoospermia to complete azoospermia [2].

46,XX male. TESE finds no sperm, and other parenthood pathways should be considered; testosterone deficiency requires replacement [6, 30].

CBAVD. Microsurgical epididymal sperm aspiration (MESA), percutaneous aspiration (PESA), TESA or TESE followed by ICSI enable biological paternity; sperm origin does not change pregnancy or miscarriage rates, counts are too low for intrauterine insemination, and isolated CBAVD has better sperm quality and ICSI outcomes than CF [3, 28]. Most CF males are infertile but not sterile because spermatogenesis may be normal [28]. In ADGRG2-related CBAVD, surgical retrieval with ICSI is likewise possible, and the first North American case resulted in two daughters [9].

Meiotic arrest and SCO genes. No therapy restores spermatogenesis. For TEX11, retrieval is predominantly negative: a multicentre study of 571 men with NOA, with literature review, included TEX11 among genes recurrently associated with failed TESE, with at least 10 negative cases [9]. TEX14 is a relatively frequent cause of azoospermia with negative TESE, and complete meiotic arrest (SYCE1, STAG3) predicts low yield [9]. In the NOA exome meta-analysis, only 5 of 45 molecularly diagnosed men with TESE data had successful retrieval [53]. Early sperm cryopreservation was suggested in the Turkish TEX15 family with declining counts, a recommendation based on one family [9]. In MCM8 or MCM9 men, ejaculated sperm should be cryopreserved when present, preservation referral made early and testosterone monotherapy avoided if fertility is desired [25].

Qualitative defects. In DNAH1-related MMAF, a retrospective cohort of 6 men with homozygous variants and 9 ICSI cycles had fertilisation of 70.8%, pregnancy of 50.0% and delivery of 37.5%, without differences from MMAF men without DNAH1 or 1431 control couples; nuclear quality (chromatin condensation, DNA fragmentation) was good [9]. In AURKC macrozoospermia, own-sperm ICSI is generally futile and exposes to polyploid embryo risk because even sperm selected for normal heads and a single flagellum were aneuploid or polyploid (Carmignac 2017); AURKC sequencing is recommended whenever at least 30% have enlarged heads and own-sperm ART avoided if mutation is confirmed, counselling donor use or adoption [9]. In DPY19L2 globozoospermia, a cohort of 34 men with 83 cycles showed ICSI with assisted oocyte activation normalised fertilisation, with similar positive hCG, ongoing pregnancy and live birth per transfer, whereas conventional ICSI performed very poorly; systematic review associated oocyte activation or intracytoplasmic morphologically selected sperm injection (IMSI) with greater success, and children were born to men with homozygous DPY19L2 deletion [9]. In SPINK2, TESE in 2008 and 2014 yielded no usable sperm [9].

Hypogonadotrophic hypogonadism. Testosterone treats hypogonadism but suppresses spermatogenesis, so when fertility is desired, gonadotrophins or pulsatile GnRH are used, inducing spermatogenesis in approximately 90–95% of men with isolated GnRH deficiency [31, 39]. Sperm rarely appear before a testicular volume of 8 mL, prior gonadotrophin treatment may shorten subsequent courses and some ANOS1 forms respond atypically; if induction fails, IVF with ICSI is used [31]. Approximately 10% of men with isolated GnRH deficiency, including Kallmann syndrome, reverse their hypogonadism after treatment withdrawal, which justifies a brief monitored treatment-free period if signs of endogenous activity emerge [31].

7.4. Management of POI of genetic origin

POI substantially reduces natural conception probability (strong), but intermittent ovarian activity may occur in non-surgical POI, so contraception is necessary if pregnancy is not desired (strong) [5]. No intervention has reliably increased ovarian activity or natural conception (strong, moderate certainty), and oocyte donation is the established option (strong) [5]. FMR1 GeneReviews mentions preliminary ethinylestradiol studies to increase spontaneous conception and very low own-oocyte IVF success in POI; contraceptive planning notes higher combined contraceptive failure than long-acting methods (intrauterine device, implant) or permanent methods [27]. When a sister donates oocytes in non-iatrogenic POI, shared genetic risk and increased stimulation cycle cancellation risk should be discussed (strong), and in an autosomal recessive disorder the sister has a 1/4 risk of also being affected [5, 9]. Fertility preservation should be discussed with at-risk women before reserve loss, but most women with established POI have no opportunity because the follicular pool is exhausted [5]. In BMP15 families, AMH and follicles may persist for several years, making early counselling and preservation useful [9]. In women with inactivating FSHR variants, gonadotrophin induction is ineffective and pregnancy is achieved through oocyte donation [9].

HT is recommended in POI until the usual age of menopause, with or without symptoms (strong), because untreated POI is associated with reduced life expectancy, mainly from cardiovascular disease [5]. To protect bone mineral density, the guideline suggests a daily dose containing at least 2 mg of oral oestradiol or 100 µg of transdermal oestradiol, or equivalent [5]. With an intact uterus, a progestogen is mandatory, at a dose proportional to that of oestrogen; the transdermal route is preferred in migraine with aura (migraine is not a contraindication), compounded bioidentical preparations are not recommended and HT is not contraceptive [9, 25]. The FMR1 GeneReviews adds that transdermal oestradiol with cyclic progesterone or with a progestogen-releasing intrauterine device mimics physiological levels, that small trials suggest superiority over combined contraception for bone density and that the transdermal route minimises thromboembolic risk [27]. In women with primary amenorrhoea, puberty is induced with increasing doses of oestrogen followed by cyclic oestrogen and progesterone; OXF already recommended HT at least until 50 years, in preference to the pill, which does not permit ovulation [11, 40]. The sources consulted give no doses for pubertal induction, which depend on paediatric protocols, including those for Turner syndrome. Calcium, vitamin D, weight-bearing exercise and smoking cessation complete bone protection; tobacco reduces ovarian reserve and brings forward the onset of FXPOI [5, 9, 27].

In Turner women, oocyte cryopreservation after controlled ovarian stimulation is the primary option after menarche with psychological maturity, at experienced centres; it should not be offered before menarche or to immature girls, and ovarian tissue cryopreservation should occur only within an approved study or with clinical ethics committee approval [43]. Oocyte cryopreservation excludes approximately 85% of patients, who develop POI before meeting these conditions, and success rate is unknown, with one live birth using cryopreserved oocytes and one pregnancy following ovarian tissue reported [43]. The guideline recommends offering AMH from diagnosis and annually if preservation is considered, with uncertain predictive utility at young ages [43]. In BPES, fertility preservation referral should occur if desired, and follow-up without ovarian reserve assessment may reduce reproductive options [12].

In oocyte defects, diagnosis prevents futile cycles. With PATL2 and TUBB8, oocyte donation was the only effective route [9]. With ZP1, stimulation does not overcome the defect but denudation technique may be adapted if a usable oocyte exists; with ZP2, conventional IVF fails and ICSI bypasses the defect, with a review of 87 women with ZP variants reporting ICSI pregnancy in 2 with ZP2, 3 with ZP1 and 3 with ZP4; one woman with a ZP3 variant and abnormal zona conceived after ICSI [9]. With WEE2, artificial oocyte activation is unestablished and failed in a compound heterozygous case [9]. With PADI6 and other maternal-effect genes, further own-oocyte attempts are expected to fail [9].

7.5. Regulatory status

Table sources: [5, 6, 9, 28, 31]. Oestradiol label information comes from GeneGuidance curation referring to each product label [9].

7.6. Trials and intervention studies

Table sources: [3, 9, 63, 66].

These studies cannot be compared indirectly: populations, designs (a randomised trial, small retrospective cohorts and highly heterogeneous meta-analyses) and outcome definitions differ. The preimplantation genetic testing for aneuploidy (PGT-A) trial is negative for its primary outcome: testing did not increase live birth, and relative pregnancy loss reduction (19.1% to 5.8% after first transfer; cumulative 22.7% to 11.1%) must be read alongside unchanged absolute live birth, selection of couples with at least four good-quality cleavage embryos or one blastocyst, 8.4% protocol deviations, one-year follow-up and an exclusively Chinese population [66]. DNAH1 and DPY19L2 cohorts are very small and non-randomised, and Klinefelter meta-analysis estimates are medians of heterogeneous studies [9, 63].

7.7. Developments in the last 12 months

Between October 2025 and October 2026, results emerged at different evidence levels. At published randomised trial level, the December 2025 BMJ study showed PGT-A does not improve live birth in ICSI for severe male factor but reduces pregnancy loss [66]. At meta-analysis level, exome yield in idiopathic NOA (15%, December 2025) and spontaneous POI (31% P/LP variants and 21% strict yield, May 2026) were published [53, 54]. At observational level, “all-in-one” exome was applied to unexplained Estonian POI with 12% yield (June 2026), and a protocol for detecting monogenic male infertility-associated comorbidities was published (May 2026) [55, 56]. At expert debate level, Schlegel and Tjagur and colleagues' commentaries (February and April 2026) discussed first-line exome [61, 62]. At guideline level, EAU published its 2026 edition as a limited 2025 update without changing genetic testing recommendations [3]. The MCM8/MCM9 GeneReviews was published in June 2026 [25].

At trial registry level (registry status, without results), ClinicalTrials.gov listed in October 2026, for Klinefelter, a phase 3 anastrozole, semaglutide and hCG trial (NCT05586802, n=150), a phase 4 pubertal testosterone gel trial (NCT06294990, n=32), phase 1 social management training in sex chromosome aneuploidies (NCT07718997) and two completed fertility preservation studies (NCT01918280, NCT01817296) [67]. For NOA, it listed autologous cryopreserved testicular tissue transplantation (NCT07364409, n=5), testicular platelet-rich plasma (NCT05479474, n=10) and phase 1/2 mesenchymal stromal cells (NCT06869863, n=80) [67]. For POI, it listed multiple early mesenchymal stem cell, exosome, platelet-rich plasma and stromal vascular fraction trials, mainly in China, a phase 3 rituximab trial in autoimmune POI (NCT07509840, n=40), another phase 3 trial of HT in adolescents with POI (NCT06851754, n=185), phase 2 low-dose prepubertal transdermal oestradiol in Turner syndrome (NCT07784582, n=15) and two Turner ovarian cryopreservation studies (NCT05740579, n=100; NCT03381300, n=106) [67]. The search identified no human gene therapy or in vitro gametogenesis trials, which does not prove non-existence [67]. Preclinically, Tex11 correction in spermatogonial stem cells restored mouse spermatogenesis (2021), pharmacological chaperones for FSHR variants were studied in vitro and in silico (2026), and differentiation studies of skin biopsy-derived induced pluripotent stem cells (iPSCs) into germ cells were described [2, 9].

7.8. Agents to avoid, pregnancy and transition

Exogenous testosterone should not be prescribed to men interested in current or future fertility (AUA/ASRM clinical principle), and testosterone monotherapy should be avoided in MCM8/MCM9 men desiring fertility [6, 25]. In men with severe oligozoospermia due to Y deletion, hormones or nutritional supplements may, according to GeneReviews, reduce counts to azoospermia [2]. Tobacco should be avoided in FMR1 premutation carriers [9]. In POI women, spontaneous pregnancy after idiopathic POI or most chemotherapy carries no greater obstetric or neonatal risk (strong), but oocyte donation pregnancy is high-risk and should be followed in an appropriate obstetric unit, disclosing oocyte origin to the team; cardiometabolic and thyroid function should be assessed before pregnancy, and women with suspected POI who are candidates for oocyte donation should undergo aetiological investigation before the procedure [5]. Turner pregnancy carries high obstetric and non-obstetric risk: OXF cited approximately 2% pregnancy death from aortic rupture or dissection in a North American series of 146 patients treated with oocyte donation (101 pregnancies), and the 2024 guideline requires comprehensive cardiac screening and counselling by maternal-fetal medicine and Turner-experienced cardiology before pregnancy planning (strong, high certainty), acknowledging oocyte donation may be inappropriate for some women [5, 35, 43]. Transition to adult care of girls with POI or Turner and boys with Klinefelter should include progressive developmentally appropriate disclosure of reduced fertility and periodic referral to a fertility specialist experienced in the condition [43, 44].

8. Reproductive Options and Family Counselling

8.1. Counselling principles

Genetic counselling is mandatory before ART in men with NOA (strong, EAU) and before ICSI with sperm from a Y deletion carrier (EAA/EMQN), covering three distinct questions: the individual's infertility cause, transmission risk of the same cause or another abnormality to offspring and implications for relatives [2, 3, 34]. Before testing, implications, the possibility of no identified cause and potential general-health findings such as CFTR, MCM9 or primary ciliary dyskinesia genes should be discussed [5, 7, 25]. Psychological support is described as “extremely important” in POI [12].

8.2. Transmission risks by mechanism

Table sources: [2, 3, 6, 9, 12, 13, 25, 26, 32, 34, 36, 43, 46].

8.3. Y chromosome and offspring

Y deletions are generally de novo except gr/gr and occur in approximately 1 in 2000 sperm from a father with normal spermatogenesis [2]. Natural transmission of complete AZFc is rare, occurring in severely oligozoospermic fathers with young highly fertile partners, corresponding according to GeneReviews to approximately 4% of severely oligozoospermic couples under these conditions [2, 39]. Through ICSI, sons inherit the same deletion, neither amplified nor corrected in subsequent generations, and daughters have no increased abnormality or infertility risk [2]. A synthesis of 25 series (1997–2019), with 268 ICSI-born children of fathers with well-documented Yq deletions, included 266 healthy children and 2 with malformations (one pulmonary atresia with right ventricular hypoplasia and one unspecified major malformation, both daughters of AZFc fathers), without ambiguous genitalia or Turner [34]. The theoretical concern is Y instability and 45,X line production: one preimplantation diagnosis study found no sex chromosome abnormalities and another more embryonic monosomy X, and a possible increased miscarriage rate was not formally tested [34]. Patsalis and colleagues (2002) described possible 45,X/46,XY or 45,X risk in AZFc men's offspring [39]. No association of AZFc with offspring intellectual, psychological or motor disturbance has been demonstrated, and the SHOX haploinsufficiency association was unreplicated; in a Chilean study, pseudoautosomal abnormalities occurred only in terminal AZFbc deletions with iso(Yp) or Y nullisomy, and neuropsychiatric disturbances were described in 5 of 7 terminal AZFbc carriers with abnormal karyotypes, still requiring validation [34]. Carrier offspring congenital defect risk is that of any infertile couple treated with ART [2].

For relatives, complete AZFc or partial AZFa and AZFb reports should recommend male relative testing because transmission is described; in complete AZFa, AZFb and AZFabc, incompatible with sperm, family screening is not indicated; in non-terminal AZFbc, sometimes compatible with spermatogenesis, obligatory transmission to sons should be explained [34]. AUA/ASRM notes that some couples prefer PGT selecting female embryos [6].

8.4. Translocations and preimplantation genetic testing

Childhood aneuploidy or UPD risk when a parent has a heterologous Robertsonian translocation depends on chromosomes involved and carrier sex:

Table source: [46] (reproduced from Gardner and Sutherland 2004). UPD occurs in 0.65% of fetuses with a balanced Robertsonian translocation; because some fetuses have normal karyotypes, overall risk is below 0.5% [46].

Studies of oocytes from carriers undergoing preimplantation diagnosis (Munné 2000) showed, for rob(13q14q), 33% unbalanced, 51% normal and 16% balanced oocytes (n=69), and for rob(14q21q), 42%, 37% and 21% (n=86) [46]. Female carriers have no increase in infertility but have more miscarriages; in a der(13;14) series, miscarriage occurred in 28% of the pregnancies of female carriers and 20% of those of the partners of male carriers, and there was no liveborn with translocation trisomy 13 among 222 pregnancies [46]. A homologous translocation, such as rob(21q21q), produces virtually only monosomic or trisomic conceptions, and the options are donor gametes or adoption [46]. The recurrence risk of a de novo translocation is below 2% when parental karyotypes are normal, and the parents of children with a translocation should be karyotyped, with cascade testing of the family [46].

The 2020 ESHRE PGT Consortium recommendations, replacing 2005 and 2011 guidance, indicate PGT-SR for carriers of reciprocal and Robertsonian translocations, insertions, deletions, duplications and inversions, using FISH, aCGH, NGS or single-nucleotide polymorphism (SNP) array in day 3 (cleavage), day 5–7 (blastocyst) or polar body biopsy [36]. With FISH, ideally three informative probes should detect all unbalanced reciprocal translocation products; aCGH detection of 3 of 4 segments is acceptable [36]. FISH, aCGH and NGS cannot distinguish normal from balanced carrier embryos, possible only with SNP-array and phased haplotyping using couple and reference relative DNA [36]. Sperm FISH in male carriers is acceptable for predicting PGT-SR efficacy, and array is less sensitive to mosaicism than NGS [36]. aCGH does not detect UPD; UPD risk is higher with chromosomes 6, 7, 11, 14, 15 and 20 and Robertsonian translocations involving 14 or 15, and prenatal UPD diagnosis should be considered [36, 46]. Residual risks (false results from recombination, mosaicism or technical error; miscarriage; viable unbalanced offspring) should be explained [36]. Diagnostic errors reported to the consortium to 2015 were mainly due to mosaicism, allele dropout and contamination [42].

In men with translocations and oligozoospermic infertility, OXF considered PGT after three or more miscarriages or when a male carrier has infertility with oligozoospermia [46]. EAU recommends PGT or amniocentesis when translocation-carrying men undergo IVF or ICSI [3]. In recurrent pregnancy loss (two or more losses), AUA/ASRM recommends male karyotyping (expert opinion) and sperm DNA fragmentation assessment (moderate, grade C), reports abnormal karyotypes in approximately 6% of infertile men and suggests considering sperm FISH for chromosomes 13, 18, 21, X and Y if somatic karyotype is normal, with uncontrolled studies suggesting PGT-A benefit [6].

8.5. PGT-A and ICSI risks

The 2025 randomised trial showed PGT-A does not increase live birth in severe male-factor ICSI but reduces pregnancy losses; 2017 OXF already cited Mastenbroek's meta-analysis (2011), where then-current aneuploidy screening (“PGS”) did not improve live births and reduced them at advanced maternal age [42, 66]. In a South Australian registry (Davies 2012), ICSI was associated with congenital defects diagnosed before 5 years in 9.9% versus 5.8% without ART (adjusted OR 1.57; 95% CI 1.30–1.90), whereas IVF had no significant increase (7.2%; adjusted OR 1.07; 0.90–1.26) [42]. ART is associated with low weight in term singleton pregnancies (OR 1.4; 95% CI 1.1–1.7 in a Danish series); a Beckwith–Wiedemann association is possible but absolute risk low (approximately 1/4000 after IVF in an Australian series), without excess in the Danish registry [42]. Mild ovarian hyperstimulation syndrome occurs in 8–23% and severe in 0.1–2% of cycles, with risk reduced by current protocols [42].

Paternal age of 40 years or more is associated with greater adverse offspring outcome risk (de novo mutations, sperm aneuploidy, structural abnormalities, congenital defects, achondroplasia, schizophrenia, autism), and AUA/ASRM recommends informing patients and, when appropriate, offering genetic counselling [6].

8.6. Klinefelter, Turner and POI

Klinefelter men's sperm have more sex chromosome aneuploidies (24,XX and 24,XY) and disomy 21 of 6.2% versus 0.4% in controls (Hennebicq 2001), although most children are euploid [32]. AUA/ASRM states no offspring sex chromosome aneuploidy has been reported after ICSI but recommends offering PGT because of potential risk; OXF indicates prenatal diagnosis if a Klinefelter man conceives, with NIPT an alternative where available [6, 32]. Recurrence risk to parents of a Klinefelter patient is below 1% [32]. Donor insemination and adoption remain alternatives [32].

In Turner women, the 2024 guideline recommends developmentally appropriate disclosure of reduced fertility, knowing conception probability relates mainly to a 46,XX line and spontaneous menarche (moderate certainty); early counselling on fertility preservation, fostering, adoption, surrogacy, oocyte or embryo donation and choosing not to have children; and referral to a Turner-experienced specialist at diagnosis and periodically [43]. PGT should be recommended or offered to women wishing to use their own oocytes (requiring sufficient reserve to obtain embryos), and prenatal diagnosis to 45,X/46,XX mosaics with spontaneous pregnancy (moderate certainty); high-risk Turner NIPT with normal ultrasound and normal or unperformed invasive testing should prompt offering maternal karyotyping, potentially revealing maternal mosaicism [43]. In Turner spontaneous pregnancies, miscarriage occurs in 29–48% versus 15% in the population, congenital abnormalities in 0–24% versus approximately 3%, preterm delivery is threefold and small for gestational age fivefold more frequent, caesarean section occurs in 35.6% versus 12% and pre-eclampsia in 6.3–11% versus 3% [43]. Recurrence risk to parents of a Turner child is not increased, and fertile mosaic Turner women may transmit X abnormalities [68]. Maternal karyotyping should be performed when a patient has 46,XX with a structurally abnormal X [35].

In non-iatrogenic POI, female relatives (sisters, daughters) should be counselled about the increased risk of POI (strong), ovarian reserve assessment may help, there are no established methods to predict or prevent POI, and some may consider family planning and fertility preservation [5]. Relatives of women with an FMR1 premutation or another identified genetic cause should receive counselling and testing [5]. The premutation places mothers, sisters and daughters at risk of FXTAS, FXPOI and associated neuropsychiatric disorders and of transmitting the full mutation, and expansion typically occurs in maternal transmission; men with a premutation transmit it to all their daughters and to none of their sons [9, 26, 69]. In MCM8/MCM9 disease, the risk to siblings is 25%, children are obligate heterozygotes and asymptomatic siblings should be tested, which in the case of MCM9 also allows cancer surveillance to be started [25]. In sex-limited autosomal dominant genes (NR5A1, DMRT1, DHX37, MAP3K1), the variant may be inherited from the mother or from a mildly affected father, 46,XX heterozygotes are usually asymptomatic (some with POI in the case of NR5A1) and 46,XY individuals affected; in the NR5A1-related 46,XX male, XX offspring are at risk of testicular or ovotesticular DSD [13, 30].

8.7. Gamete donation, recurrence and minors

Sister oocyte donation requires discussion of shared genetic risk (strong), and in recessive disease the sister may be affected [5, 9]. In the SRY-positive 46,XX male, recurrence is generally zero because X/Y exchange is de novo; inheritance occurs only rarely when SRY is translocated to an autosome or fertility preserved [30]. For minors, disclosure should be progressive and developmentally appropriate, preservation decisions shared with child and family, and prepubertal testicular tissue cryopreservation in Klinefelter boys remains experimental [3, 43].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

Frequency estimates for genetic infertility causes depend on denominator. Birth prevalence (Klinefelter, Turner), frequency in infertile men referred to tertiary centres (AZF deletions, chromosomal abnormalities), diagnostic yield in an exome-selected cohort (NOA or POI genes) and population allele frequency (FSHR, AURKC, MCM8/MCM9) are not mutually comparable.

For POI prevalence, the 2024 guideline notes that population characteristics such as ethnicity may influence estimates [5]. For Y microdeletions, EAA/EMQN explains variation from 2% to over 10% by sample composition (more azoospermic men, greater frequency), and the 10–15% frequency in idiopathic azoospermia or severe oligozoospermia in 2017 OXF reflects more selected series than current ones [34, 39]. Kallmann estimates differ by an order of magnitude because OXF presents a frequency and the Finnish study a minimum diagnostic incidence [31, 39]. The Brazilian source's estimate that Klinefelter accounts for 3% of infertile men is consistent with 2.6% in EAU's single-centre series [3, 33]. The Brazilian source also presents a chromosomal constitution table exceeding 100% because of a transcription defect; those values are not reproduced here [33].

9.2. Founder effects and ancestry

Best-characterised founder effects are FSHR p.(Ala189Val) in northern and northeastern Finland (carriers approximately 1 in 85; allele frequency 0.96% in Finns, rare in Switzerland and absent in Danish and Chinese samples), AURKC c.145del in the Maghreb, with approximately 1 carrier in 50 — in a series of 599 Algerians from an ART clinic, 11 of 14 men with typical macrozoospermia were homozygous, accounting for 2.7% of abnormal semen analyses, more than the expected 1.6% Klinefelter and 0.23% microdeletions in that cohort —, the 22.6 kb SPATA16 deletion in Tunisians, ERAL1 p.(Asn236Ile) in a Dutch isolate and unaffected gr/gr fixation in D2b and Q haplogroups in Japan and parts of China [9, 11, 34]. The founding DNAH1 series comprised North African individuals, and consanguinity explains part of high exome yields in some NOA cohorts [41, 53]. CFTR carrier frequency varies with ancestry, changing residual risk after negative partner testing [3, 6]. Loss-of-function MCM8 allele frequency is highest in African and African American individuals (up to 5.5/100 000), and MCM9 in Finns (up to 5.7/100 000) [25]. Large POI exome studies come from China (1030 Shandong women) and Estonia, and NOA studies from Germany, the Netherlands, Estonia and GEMINI, limiting yield generalisation elsewhere [7, 10, 52, 53, 55, 60]. EAU therefore requires geographically and ethnically diverse cohort validation before recommending clinical exome [3].

9.3. Portugal and Brazil

GEMINI included Portuguese centres (i3S/IPATIMUP and Faculty of Medicine, University of Porto; Instituto Nacional de Saúde Doutor Ricardo Jorge and NOVA Medical School, Lisbon), but the consulted text provides no Portugal-specific numbers [52]. The Brazilian source estimates Klinefelter at 1/448 male births and describes Turner reproductive options, including oocyte and ovarian tissue cryopreservation with residual function [33, 68]. Consulted sources include no Brazilian Y deletion, CBAVD CFTR or POI genetic data, which does not mean no studies are published.

9.4. Special populations

Childhood cancer survivors and men with persistent azoospermia after gonadotoxic treatment form a group where genetic and acquired causes overlap: micro-TESE is an option in persistent post-gonadotoxic azoospermia (strong, grade B, AUA/ASRM), and an acquired diagnosis does not obviate Y testing with azoospermia or severe oligozoospermia [6, 34]. Iatrogenic POI may warrant pretreatment fertility preservation (conditional) [5]. Men with CF and women with CF receiving modulators are changing populations, with recently increased pregnancies [28]. People with DSD require interdisciplinary teams, and 46,XY women with Müllerian structures may conceive through oocyte donation [9, 13]. Advanced paternal age is an emerging fertility and offspring risk factor [3, 6].

9.5. European reference networks and patient associations

Endo-ERN, the European reference network for rare endocrine conditions, has a Sex Development & Maturation thematic group relevant to Klinefelter, Turner, DSD, hypogonadism and POI [37]. ERN ITHACA is relevant when families include syndromes with congenital abnormalities or intellectual disability, such as fragile X syndrome [38]. Patient associations include Fertility Europe, RESOLVE (The National Infertility Association, USA), Associação Portuguesa de Fertilidade, Daisy Network (POI, United Kingdom), Turner Syndrome Support Society (United Kingdom), Turner Syndrome Foundation (USA), AXYS (X and Y chromosome variations, USA), National Fragile X Foundation (USA) and Cystic Fibrosis Europe [70–78]. Orphanet maintains the entity and specialist clinic inventory [1].

10. Illustrative Clinical Case

Tjagur and colleagues from Tartu University Hospital (Estonia) described in 2025 the “diagnostic odyssey” of a man with 45,X/46,XY mosaicism [57]. The 29-year-old patient of European origin presented with sudden right hemiscrotal enlargement, an inguinal hernia corrected surgically. Investigation revealed repeat-confirmed azoospermia, semen volume 3.5 mL, distal penile shaft hypospadias and testicular volumes of 10 and 8 mL by orchidometer (8.6 and 7.1 mL by ultrasound) with microcalcifications. FSH was 31.8 IU/L (reference 1.5–12.4), LH 12.96 IU/L (1.7–8.6) and testosterone 11.31 nmol/L (8.64–29.0). He was 152 cm tall, approximately 30 cm below the Estonian mean, with relative macrocephaly, short limbs and normal cognition; autoimmune thyroiditis was diagnosed at 32 years. Transrectal ultrasound and MRI showed prostate volumes of 14.3 and 11.8 mL with macrocalcifications, left seminal vesicle hypoplasia, absent distal left vas deferens and ampulla, and dilated right ampulla and ejaculatory duct (article figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC12905614/figure/fig1/).

Initial 12-metaphase karyotyping was normal 46,XY; there were no AZF microdeletions or biallelic CFTR variants. Exome requested for a monogenic cause found no causal variant, but read distribution predicted 45,X/46,XY mosaicism, with X/autosome coverage ratio 0.53 and Y/autosome 0.18. The 45,X line was estimated at 67% by exome, 60% by repeat karyotype (18 of 30 metaphases) and CMA, and 55% by interphase FISH in buccal mucosa (63 of 114 nuclei; article figure 2, X probes green and Y orange: https://pmc.ncbi.nlm.nih.gov/articles/PMC12905614/figure/fig2/). The patient was referred to endocrinology, cardiology and otorhinolaryngology; echocardiography was normal; and because of gonadal and breast neoplasia risk, annual tumour markers (alpha-fetoprotein, lactate dehydrogenase and hCG, normal over two years) and testicular ultrasound screening began [57].

The case illustrates several points of this article. First, a 12-metaphase karyotype did not exclude 55–67% mosaicism, which the repeat karyotype with 30 metaphases identified; second, the combination of short stature, hypospadias, small testes with microcalcifications and unilateral Wolffian anomalies in an azoospermic man corresponds to the warning signs of sex chromosome mosaicism described in section 4; third, the diagnosis changed surveillance (cardiological, endocrine and oncological) beyond the reproductive question [7, 57]. The case was the starting point of the debate between Schlegel, who argued that a well-performed standard karyotype and Y testing are sufficient to decide the management of NOA and considered universal exome sequencing unnecessary, and the authors, who advocated exome sequencing as first line only in severe spermatogenic failure with a suspected genetic cause [61, 62]. Detection of the mosaicism by exome sequencing in this patient is not presented as routine: no guideline currently recommends exome sequencing in place of the karyotype, which remains necessary for balanced translocations [3, 7].

11. Prognosis and Long-Term Follow-Up

11.1. Reproductive prognosis

Reproductive prognosis depends directly on genetic diagnosis. In males, complete AZFa or AZFb deletions, 46,XX males and most complete meiotic arrest genes imply zero or very low own-gamete probability, whereas complete AZFc (approximately 50% retrieval), Klinefelter (median retrieval 44% and live birth 11.1%), CBAVD (retrieval almost always possible) and DNAH1-related MMAF (delivery in 37.5% of cycles in a small cohort) allow biological paternity with ICSI in variable proportions [3, 9, 34, 63]. In general NOA, retrieval reaches up to 50% and live birth up to 28% per ICSI cycle [3]. Combined classical methods (karyotype, AZF, CFTR) yield approximately 20–25% in azoospermia and approximately 10% in extreme oligozoospermia (<1 million/mL); exome studies in crypto/azoospermia without classical causes add monogenic diagnosis in 8.5–15.7% [7]. Nevertheless, over three-quarters of NOA men assessed by exome remain unexplained, warranting periodic data reanalysis [7].

In women with POI, natural conception is unlikely but possible (up to 12.6% conceive after FXPOI diagnosis), and oocyte donation is established [5, 27]. In Turner syndrome, spontaneous pregnancy occurs in approximately 10% and oocyte cryopreservation is accessible only to a minority [43].

11.2. General health prognosis

Genetic infertility diagnosis has implications beyond reproduction. Untreated POI is associated with reduced life expectancy, mainly cardiovascular, and osteoporosis; in follow-up of 26 Finnish women with FSHR p.(Ala189Val), late-started HT (median 18 years) used for 20–22 years did not prevent osteopenia in 9 of 14, without excess cardiovascular risk factors or diabetes [5, 9]. Men with NOA have greater long-term cardiometabolic disease, cancer and mortality risk [3]. Biallelic MCM9 carriers risk early colorectal and gastric polyposis and cancer, and girls with MCM8/MCM9 or gonadal dysgenesis with Y material risk germ cell tumours [25, 45]. Non-functional dysgenetic gonads in 46,XY DSD should be removed because of gonadoblastoma risk or kept under surveillance, with annual ultrasound among described options [9]. gr/gr carriers have increased testicular germ cell tumour risk, and Klinefelter men metabolic, cardiovascular and haematological neoplasia risk [3, 34]. CFTR-related CBAVD is accompanied in a minority by adult respiratory or pancreatic disease [28].

11.3. Surveillance

Surveillance of the non-reproductive manifestations of Klinefelter syndrome, Turner syndrome, fragile X syndrome, CF, primary ciliary dyskinesia and Kallmann syndrome follows the respective specific recommendations.

12. Summary and Final Considerations

Genetic infertility encompasses chromosomal, Y-linked, X-linked and autosomal causes converging on similar reproductive phenotypes but with very different prognoses and offspring risks. In males, repeated semen analysis, FSH, karyotype, AZF microdeletion testing and CFTR testing with absent vas deferens remain the basis recommended by EAU 2026, AUA/ASRM 2024 and EAA/EMQN 2023; guidelines differ in karyotype concentration thresholds (<5 million/mL in EAU recommendations, <10 million/mL in the same guideline text, <5 million/mL with clinical criteria in AUA/ASRM) and converge in recommending Y testing below 1 million/mL. Y deletion type determines whether surgical retrieval is meaningful: zero in complete AZFa and AZFb, approximately 50% in complete AZFc, with obligatory transmission to sons. In females, karyotype and specific FMR1 premutation testing are recommended in all non-iatrogenic POI, with NGS a conditional option.

Exome and multigene panels have increased diagnostic yield — approximately 15% in idiopathic NOA and 21–31% in spontaneous POI in recent highly heterogeneous meta-analyses —, identify causes with prognostic value for TESE (TEX11, TEX14, meiotic arrest genes) and reproductive technique (AURKC, DPY19L2, oocyte genes), and reveal comorbidities (MCM9, CFTR, primary ciliary dyskinesia genes). They replace neither karyotyping, indispensable for balanced translocations, nor targeted FMR1 testing, and their first-line position remains debated. Interpretation requires attention to revised inheritance models (BMP15, NOBOX), contested pathogenicity (the TEX11 exon 10–12 deletion, SYCP3) and inconsistent normalisation (CFTR 5T), and database errors such as Orphanet's autosomal recessive inheritance assignment for FXPOI or GenCC's for ADGRG2.

There is no targeted pharmacological treatment. Management combines micro-TESE and ICSI, oocyte activation in selected cases, POI HT with at least 2 mg oral or 100 µg transdermal oestradiol daily until usual menopausal age, fertility preservation while windows remain, gamete donation and PGT. The 2025 randomised trial showed PGT-A does not increase live birth in severe male-factor ICSI, although reducing pregnancy losses. Genetic counselling before assisted reproduction should cover cause, transmission to children and relatives' implications, and long-term surveillance should include bone, cardiovascular, endocrine and, for some entities, oncological health.

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