1. Enrichment of rare variants in nuclear-encoded mitochondrial metabolism genes in patients with early-onset or familial parkinson’s diseaseGaber Bergant, Vesna M. Van Midden, Polina Tsygankova, Dorian Laslo, Valentino Rački, Dejan Georgiev, Eliša Papić, Marija Branković, Milena Janković, Marina Svetel, Nataša Teran, Natasa Dragasević Misković, Igor N. Petrović, Aleš Maver, Ivana Novaković, Zvezdan Pirtošek, Martin Rakuša, Vladimira Vuletić, Borut Peterlin, 2026, izvirni znanstveni članek Ključne besede: mitochondrial metabolism, mitochondrial variants, mutation burden analysis
Objavljeno v DiRROS: 05.05.2026; Ogledov: 109; Prenosov: 69
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2. 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: 265; Prenosov: 153
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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: 357; Prenosov: 236
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4. Increased burden of rare variants in GWAS associated genes in familial multiple sclerosisAleksander Turk, Aleš Maver, Peter Juvan, Jelena Drulović, Sarlota Mesaros, Ivana Novaković, Nada Starčević-Čizmarević, Smiljana Ristić, Ivana Stanković Matić, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease affecting the central nervous system with many known genetic risk factors. Although genome-wide association studies (GWAS) have identified common genetic variants with small effects associated with MS, the role of rare variants with large effects in MS aetiology remains underexplored. We hypothesized that rare variants in MS-associated genes from GWAS studies (GWAS-associated genes) are more likely to contribute to familial MS (FMS) risk than to sporadic MS (SMS). Therefore, we aimed to assess the burden of rare, predicted pathogenic (RPP) variants in GWAS-associated genes in FMS and SMS patients compared to controls. Rare genetic variants in 111 GWAS-associated genes were assessed in 87 FMS, 89 SMS and 3866 control cases. We demonstrate that RPP variants were significantly overrepresented in the FMS cohort whereas their frequency was not increased in the SMS cohort compared to controls (p-values 5.27 × 10− 74 and 1.00, respectively). Six genes (ALPK2, ANKRD55, INTS8, IQCB1, JADE2, and MALT1) significantly contributed to the burden of RPP in the FMS group. We conclude that rare variants in genes identified by GWAS might contribute to the genetic predisposition of familial MS patients.
Ključne besede: multiple sclerosis, burden analysis, whole exome sequencing (WES), rare variants, rare pathological changes, candidate genes
Objavljeno v DiRROS: 12.11.2025; Ogledov: 473; Prenosov: 264
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