Browsing by Author "Peterlin, Borut (55816646000)"

Parkinson’s disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected. © 2022, The Author(s).

Parkinson’s disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected. © 2022, The Author(s).

Background: Preterm birth is the largest contributor to newborn mortality, morbidity, and hospitalization in the first year of life worldwide. Previous studies have suggested the importance of genetic variation in the angiotensin-converting enzyme gene, including the angiotensin-converting enzyme gene insertion/deletion polymorphism, in association with preterm birth. The angiotensin-converting enzyme is a key component of the renin-angiotensin system that is involved in blood pressure homeostasis during pregnancy and also affects risk factors of preterm birth, including the regulation of fibrinolytic system, uteroplacental circulation, vascularization of the placenta, and inflammation. Objective: The results of previous studies investigating the association between the insertion/deletion polymorphism and susceptibility to preterm birth have been inconsistent, therefore, we have performed a case-control study and conducted a meta-analysis of related studies to clarify this association. Study design: In a case-control genetic association study, performed on 217 women with a history of preterm birth and 158 women who experienced full-term pregnancy, the significances of associations between allelic and genotype frequencies and preterm birth were determined using Chi-square tests. Following the case-control study, PubMed, Scopus, Google Scholar, and HugeNavigator databases were systematically searched to identify relevant studies. Altogether, four eligible studies involving 369 cases and 559 controls were included in the meta-analysis. The strength of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism for preterm birth was estimated by odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs), using a fixed-effects model (Mantel-Haenszel method). Results: In our case-control study we did not detect a significant association of angiotensin-converting enzyme insertion/deletion alleles and genotypes with preterm birth. The results of the meta-analysis showed a significant association between the angiotensin-converting enzyme gene insertion/deletion and the risk of preterm birth under allelic, dominant, and recessive comparison genetic models (D vs. I: OR = 1.35, 95% CI = 1.11–1.65, p = 0.0033; DD + ID vs. II: OR = 1.52, 95% CI = 1.08–2.15, p = 0.0161; DD vs. ID + II: OR = 1.48, 95% CI = 1.07–2.04, p = 0.0184). Conclusions: The present meta-analysis suggests that the insertion/deletion polymorphism of the angiotensin-converting enzyme gene in mothers might be associated with preterm birth, however, further well-designed large replication studies involving various ethnicities are needed to confirm this association. © 2018 Elsevier B.V.

Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient’s peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient’s visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient’s PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control’s PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient’s PBMCs. © 2025 by the authors.

Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient’s peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient’s visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient’s PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control’s PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient’s PBMCs. © 2025 by the authors.

Purpose: We sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility. Methods: We retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis. Results: Extended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis. Conclusion: We show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload. © 2018 American College of Medical Genetics and Genomics.

Introduction: In this study we aimed to perform the first research on the current state of compulsory basic and clinical courses in genetics for medical students offered at medical faculties in six Balkan countries with Slavic languages (Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, Serbia, and Slovenia). Materials and Methods: The study was conducted from June to September 2021. One representative from each country was invited to collect and interpret the data for all medical faculties in their respective country. All representatives filled a questionnaire, which consisted of two sets of questions. The first set of questions was factual and contained specific questions about medical faculties and design of compulsory courses, whereas the second set of questions was more subjective and inquired the opinion of the representatives about mandatory education in clinical medical genetics in their countries and internationally. In addition, full course syllabi were analysed for course aims, learning outcomes, course content, methods for student evaluation and literature. Results: Detailed analysis was performed for a total of 22 medical faculties in Bosnia and Herzegovina (6), Croatia (4), Montenegro (1), North Macedonia (3), Serbia (6), and Slovenia (2). All but the two medical faculties in Slovenia offer either compulsory courses in basic education in human genetics (16 faculties/courses) or clinical education in medical genetics (3 faculties/courses). On the other hand, only the medical faculty in Montenegro offers both types of education, including one course in basic education in human genetics and one in clinical education in medical genetics. Most of the basic courses in human genetics have similar aims, learning outcomes and content. Conversely, clinical courses in medical genetics are similar concerning study year position, number of contact hours, ECTS (European Credit Transfer and Accumulation System) and contents, but vary considerably regarding aims, learning outcomes, ratio of types of classes, teaching methods and student evaluation. Conclusion: Our results emphasise the need for future collaboration in reaching a consensus on medical genetics education in Balkan countries with Slavic languages. Further research warrants the analysis of performance of basic courses, as well as introducing clinical courses in medical genetics to higher years of study across Balkan countries. Copyright © 2022 Pereza, Terzić, Plaseska-Karanfilska, Miljanović, Novaković, Poslon, Ostojić and Peterlin.

Introduction: In this study we aimed to perform the first research on the current state of compulsory basic and clinical courses in genetics for medical students offered at medical faculties in six Balkan countries with Slavic languages (Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, Serbia, and Slovenia). Materials and Methods: The study was conducted from June to September 2021. One representative from each country was invited to collect and interpret the data for all medical faculties in their respective country. All representatives filled a questionnaire, which consisted of two sets of questions. The first set of questions was factual and contained specific questions about medical faculties and design of compulsory courses, whereas the second set of questions was more subjective and inquired the opinion of the representatives about mandatory education in clinical medical genetics in their countries and internationally. In addition, full course syllabi were analysed for course aims, learning outcomes, course content, methods for student evaluation and literature. Results: Detailed analysis was performed for a total of 22 medical faculties in Bosnia and Herzegovina (6), Croatia (4), Montenegro (1), North Macedonia (3), Serbia (6), and Slovenia (2). All but the two medical faculties in Slovenia offer either compulsory courses in basic education in human genetics (16 faculties/courses) or clinical education in medical genetics (3 faculties/courses). On the other hand, only the medical faculty in Montenegro offers both types of education, including one course in basic education in human genetics and one in clinical education in medical genetics. Most of the basic courses in human genetics have similar aims, learning outcomes and content. Conversely, clinical courses in medical genetics are similar concerning study year position, number of contact hours, ECTS (European Credit Transfer and Accumulation System) and contents, but vary considerably regarding aims, learning outcomes, ratio of types of classes, teaching methods and student evaluation. Conclusion: Our results emphasise the need for future collaboration in reaching a consensus on medical genetics education in Balkan countries with Slavic languages. Further research warrants the analysis of performance of basic courses, as well as introducing clinical courses in medical genetics to higher years of study across Balkan countries. Copyright © 2022 Pereza, Terzić, Plaseska-Karanfilska, Miljanović, Novaković, Poslon, Ostojić and Peterlin.

Study question: Are de novo mutations in the human genome associated with male infertility?. Summary answer: We identified de novo mutations in five candidate genes: SEMA5A, NEURL4, BRD2, CD1D, and CD63. What is known already: Epidemiological and genetic studies have consistently indicated contribution of genetic factors to the etiology of male infertility, suggesting that more than 1500 genes are involved in spermatogenesis. Study design, size, duration: First, we searched for de novo mutations in patients with idiopathic azoospermia with whole-exome sequencing (WES). To evaluate the potential functional impact of de novo identified mutations, we analyzed their expression differences on independent testis samples with normal and impaired spermatogenesis. In the next step, we tested additional group of azoospermic patients for mutations in identified genes with de novo mutations. In addition to the analysis of de novo mutations in patients with idiopathic azoospermia, we considered other models of inheritance and searched for candidate genes harboring rare maternally inherited variants and biallelic autosomal and X-chromosome hemizygous variants. Participants/materials, setting, methods: We performed WES in 13 infertile males with idiopathic azoospermia and their parents. Potential functional impact of de novo identified mutations was evaluated by global gene expression profiling on 20 independent testis samples. To replicate the results, we performed WES in further 16 independent azoospermic males, which were screened for the variants in the same genes. Library preparation was performed with Nextera Coding Exome Capture Kit (Illumina), with subsequent sequencing on Illumina HiSeq 2500 platform. Main results and the role of chance: We identified 11 de novo mutations in 10 genes of which 5 were considered potentially associated with azoospermia: SEMA5A, NEURL4, BRD2, CD1D, and CD63. All candidate genes showed significant differential expression in testis samples composed of patients with severely impaired and normal spermatogenesis. Additionally, we identified rare, potentially pathogenic mutations in the genes previously implicated in male infertility—a maternally inherited heterozygous frameshift variant in FKBPL gene and inframe deletion in UPF2 gene, homozygous frameshift variant in CLCA4 gene, and a heterozygous missense variant NR0B1 gene, which represent promising candidates for further clinical implication. Limitations of the study, reasons for caution: We provided limited functional support for involvement of de novo identified genes in pathogenesis of male infertility, based on expression analysis. Additionally, the sample size was limited. Wider implications of the findings: We provide support that de novo mutations might contribute to male infertility and propose five genes as potentially implicated in its pathogenesis. © 2020 American Society of Andrology and European Academy of Andrology

Study question: Are de novo mutations in the human genome associated with male infertility?. Summary answer: We identified de novo mutations in five candidate genes: SEMA5A, NEURL4, BRD2, CD1D, and CD63. What is known already: Epidemiological and genetic studies have consistently indicated contribution of genetic factors to the etiology of male infertility, suggesting that more than 1500 genes are involved in spermatogenesis. Study design, size, duration: First, we searched for de novo mutations in patients with idiopathic azoospermia with whole-exome sequencing (WES). To evaluate the potential functional impact of de novo identified mutations, we analyzed their expression differences on independent testis samples with normal and impaired spermatogenesis. In the next step, we tested additional group of azoospermic patients for mutations in identified genes with de novo mutations. In addition to the analysis of de novo mutations in patients with idiopathic azoospermia, we considered other models of inheritance and searched for candidate genes harboring rare maternally inherited variants and biallelic autosomal and X-chromosome hemizygous variants. Participants/materials, setting, methods: We performed WES in 13 infertile males with idiopathic azoospermia and their parents. Potential functional impact of de novo identified mutations was evaluated by global gene expression profiling on 20 independent testis samples. To replicate the results, we performed WES in further 16 independent azoospermic males, which were screened for the variants in the same genes. Library preparation was performed with Nextera Coding Exome Capture Kit (Illumina), with subsequent sequencing on Illumina HiSeq 2500 platform. Main results and the role of chance: We identified 11 de novo mutations in 10 genes of which 5 were considered potentially associated with azoospermia: SEMA5A, NEURL4, BRD2, CD1D, and CD63. All candidate genes showed significant differential expression in testis samples composed of patients with severely impaired and normal spermatogenesis. Additionally, we identified rare, potentially pathogenic mutations in the genes previously implicated in male infertility—a maternally inherited heterozygous frameshift variant in FKBPL gene and inframe deletion in UPF2 gene, homozygous frameshift variant in CLCA4 gene, and a heterozygous missense variant NR0B1 gene, which represent promising candidates for further clinical implication. Limitations of the study, reasons for caution: We provided limited functional support for involvement of de novo identified genes in pathogenesis of male infertility, based on expression analysis. Additionally, the sample size was limited. Wider implications of the findings: We provide support that de novo mutations might contribute to male infertility and propose five genes as potentially implicated in its pathogenesis. © 2020 American Society of Andrology and European Academy of Andrology

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources. © The Author(s) 2019.

Aim: The aim of this study was to assess the prevalence of familial MS (fMS) in Belgrade MS population, discern the differences between the persons with fMS and sporadic MS, and to detect the presence of anticipation phenomenon in fMS patients. Methods: The data on the demographic and clinical characteristics of MS patients was obtained from the Belgrade MS population Registry. In cases of vertical transmission of MS, the family members were divided into the younger and older generation, in order to assess the potential presence of anticipation phenomenon. To adjust for follow-up time bias, a secondary analysis including only patients who had the onset of symptoms before 39 years (75.percentile), and those who were 39 + years, was performed. Results: The prevalence of fMS in Belgrade MS population is 6.4%. FMS cases had earlier age at MS symptom onset (30.4 vs. 32.3 years) compared to sporadic MS cohort. When comparing fMS cases across generations, the younger generation had significantly lower age at onset compared with the older one (25.8 vs. 35.7 years, p < 0.001). After adjustment for the different length of the follow-up, the difference in age at symptom onset between the groups was reduced, but it still existed and was statistically significant (30.0 years in younger vs. 36.4 years in older generation, p = 0.040). Conclusion: In our study, the analysis of fMS cases across generations, showed an earlier age of symptom onset in the younger generation, even after adjustment. These results indicate the possibility of existence of anticipation phenomenon. © Fondazione Società Italiana di Neurologia 2024.

Background: Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. Methods: A case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. Results: A total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22–3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. Conclusion: Our study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease. © 2023

Background: Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. Methods: A case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. Results: A total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22–3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. Conclusion: Our study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease. © 2023

Purpose: 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. Copyright © 2025 Korean Society for Sexual Medicine and Andrology.

Purpose: 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. Copyright © 2025 Korean Society for Sexual Medicine and Andrology.

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its’ paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly. © 2018 Elsevier Masson SAS

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its’ paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly. © 2018 Elsevier Masson SAS

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics. © 2024 by the authors.

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics. © 2024 by the authors.