1. Genetic testing for monogenic forms of male infertility contributes to the clinical diagnosis of men with severe idiopathic male infertilityRebeka Podgrajšek, Alenka Hodžić, Aleš Maver, Martin Štimpfel, Aleksander Andjelić, Olivera Miljanović, Momčilo Ristanović, Ivana Novaković, Dijana Plašeska Karanfilska, Predrag Noveski, Saša Ostojić, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: In recent years, many genes have been associated with male infertility; however, testing of monogenic forms has not yet been clinically implemented in the diagnosis of severe forms of idiopathic male infertility, as the diagnostic utility has not been established yet. The aim of this study was therefore to answer if the implementation of genetic testing for monogenic forms of male infertility could contribute to the clinical diagnosis of men with severe forms of idiopathic male infertility. Materials and Methods: Based on the ClinGene curation protocol, we defined a panel of genes with sufficient evidence for the involvement with severe male infertility. We tested the 21-gene panel in a representative multicentric cohort of men with significantly impaired spermatogenesis. We performed whole exome sequencing on 191 infertile men with severe forms of idiopathic male infertility; non-obstructive azoospermia, and severe oligozoospermia (<5 million spermatozoa/mL). The control group consisted of 216 men who fathered a child. DNA was prepared based on the Twist CORE exome protocol and sequenced on the Illumina NovaSeq 6000 platform. Variants were classified using the Association for Clinical Genomic Science (ACGS) Best Practice Guidelines for Variant Classification in Rare Disease 2020. Results: We identified potential monogenic disease-causing variants in four infertile men. Pathogenic/likely pathogenic variants in STAG3 (c.2776C>T, p.Arg926*; c.2817delG, p.Leu940fs), MSH4 (c.1392delG, p.Ile465fs; c.2261C>T, p.Ser754Leu), TEX15 (c.6848_6849delGA, p.Arg2283fs; c.6271dupA, p.Arg2091fs), and TEX14 (c.1021C>T, p.Arg341*) genes were found. Conclusions: In the present multicentric cohort study, a monogenic cause in 2.1% of infertile men was identified. These findings confirm the utility of monogenic testing and suggest the clinical use of monogenic testing for men with severe forms of idiopathic male infertility.
Ključne besede: azoospermia, genetic testing, male, meiosis
Objavljeno v DiRROS: 18.03.2026; Ogledov: 195; Prenosov: 114
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2. The role of DNA mismatch repair mutS/mutL homolog genes in spermatogenesis and male infertility : a systematic review and cohort studyRebeka Podgrajšek, Alenka Hodžić, Aleš Maver, Martin Štimpfel, Aleksander Andjelić, Olivera Miljanović, Momčilo Ristanović, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: Background: Recent research in male infertility genetics has identified numerous candidate genes, some of which were also involved in DNA repair. Mismatch repair (MMR) genes, such as MSH4 and MSH5, have been linked to male infertility due to their role in meiosis, suggesting that other MMR genes may also contribute to impaired spermatogenesis. To investigate the role of MMR genes in male infertility, we first conducted a systematic review focusing on their involvement in impaired spermatogenesis, which was followed by a multicenter cohort study assessing the occurrence of rare deleterious variants in MMR genes among men with severely impaired fertility. The present study aimed to assess the contribution of MMR genes to male infertility and to evaluate their potential clinical utility in the diagnostic workup of men with severely impaired fertility. Methods: A systematic review was conducted through a PubMed database search with a focus on the role of MMR genes in spermatogenesis. We additionally prepared a cohort study, including whole-exome sequencing data from 244 infertile men presenting azoospermia or severe oligozoospermia (< 5 million spermatozoa/ml). Rare, deleterious variants in MMR genes were classified using the ACGS Guidelines for Variant Classification 2020. Results: Following a systematic review of the literature, we gathered robust evidence supporting the strong involvement of MSH4 and MSH5 variants in male infertility, moderate evidence for MLH3, and limited evidence for other MMR genes. From our cohort, we identified likely pathogenic or pathogenic variants in two individuals: one with two MSH4 variants and another with a PMS2 variant. Conclusions: The present study identifies MSH4 and MSH5 as strong candidate genes for male infertility, supporting the integration of their testing into the clinical diagnosis of infertile men, particularly those exhibiting non-obstructive azoospermia. Although current evidence suggests that genetic variants in most MMR genes do not cause infertility, genetic defects in MMR genes can still impair spermatogenesis due to their critical role in sperm DNA repair and maintenance of genome integrity.
Ključne besede: male infertility, spermatogenesis, mismatch repair, gens, MSH, MLH
Objavljeno v DiRROS: 22.12.2025; Ogledov: 313; Prenosov: 185
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3. ACE gene and male infertility : a South Slavic case-control study and multi-omics data integrationTanja Kunej, Rebeka Podgrajšek, Helena Jaklič, Alenka Hodžić, Martin Štimpfel, Olivera Miljanović, Momčilo Ristanović, Ivana Novaković, Dijana Plašeska Karanfilska, Predrag Noveski, Saša Ostojić, Alena Buretić-Tomljanović, Antun Gršković, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: Components of the renin-angiotensin system (RAS) are expressed in both female and male reproductive tracts, with angiotensin I converting enzyme (ACE) being an important component for male reproductive function, as shown in animal models. The most studied ACE polymorphism is the Alu insertion-deletion (I/D), which has been proposed to have a negative effect on male fertility. Given the conflicting evidence in the literature, we conducted a multicentric case-control study to investigate the association between the ACE Alu I/D polymorphism and impaired spermatogenesis. Using PCR amplification and agarose electrophoresis, we genotyped the ACE gene Alu I/D polymorphism in 745 South Slavic men. The study group consisted of 457 patients with impaired spermatogenesis, 239 with non-obstructive azoospermia (NOA) and 218 with oligoasthenoteratozoospermia (OAT) and a control group of 288 fertile men. No association was found between the Alu I/D polymorphism and these semen phenotypes, suggesting that it is not associated with NOA or severe OAT in this cohort. To provide a broader regulatory context, we also developed an integrative atlas of ACE regulatory elements by in silico multi-omics analysis using genomics databases and bioinformatics tools. Data integration revealed various regulatory mechanisms at multiple omics levels, including genomics, epigenomics, miRNAomics, transcriptomics, proteomics and epiproteomics. These include genomic variants with predicted deleterious effects, a CpG island, microRNAs (miRNAs) and post-translational modifications (PTMs). In addition, protein interaction analysis revealed that ACE is indirectly linked to several proteins previously associated with male infertility and is also targeted by miRNA previously associated with oligozoospermia. This comprehensive, multi-faceted approach, combining genetic association analysis with bioinformatics, provides insights into ACE regulation in its broader molecular context. These results emphasize the importance of further integrative multi-omics and systems biology research to better understand the role of ACE in male reproductive function.
Ključne besede: angiotensin I converting enzyme (ACE), male infertility, azoospermia, oligozoospermia, multi-omics
Objavljeno v DiRROS: 09.12.2025; Ogledov: 321; Prenosov: 192
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4. Value of optical genome mapping (OGM) for diagnostics of rare diseases : a family case reportAnja Kovanda, Olivera Miljanović, Luca Lovrečić, Aleš Maver, Alenka Hodžić, Borut Peterlin, 2024, drugi znanstveni članki Povzetek: Optical genome mapping (OGM) is a novel method enabling the detection of structural genomic variants. The method is based on the laser image acquisition of single, labeled, high-molecular-weight DNA molecules and can detect structural genomic variants such as translocations, inversions, insertions, deletions, duplications, and complex structural rearrangements. We aim to present our experience with OGM at the Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Slovenia. Since its introduction in 2021, we have used OGM for the testing of facioscapulohumeral muscular dystrophy 1, characterization and resolution of variants identified by other technologies such as microarrays, exome and genome next-generation sequencing, karyotyping, as well as testing of rare disease patients in whom no genetic cause could be identified using these methods. We present an example family case of two previously undiagnosed male siblings with an overlapping clinical presentation of thrombocytopenia, obesity, and presacral teratoma. After karyotyping, microarray analysis and next-generation sequencing, by using OGM, a maternally inherited cryptic translocation t(X;18)(q27.1;q12.2) was identified in both brothers. Despite an extended segregation analysis, based on strictly applied ACMG criteria and ClinGen guidelines, the identified translocation remains a variant of unknown significance. Despite the remaining limitations of OGM, which will hopefully be resolved by improvements in databases of known benign SV variation and the establishment of official guidelines on the clinical interpretation of OGM variants, our work highlights the complexity of the diagnostic journey, including this novel method, in rare disease cases.
Ključne besede: optical genome mapping, OGM, structural variants, SV, genomic variants, rare disease genetic testing
Objavljeno v DiRROS: 04.12.2025; Ogledov: 405; Prenosov: 232
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