Male infertility is a multifactorial disorder affecting approximately 15% of couples worldwide and contributing to nearly 50% of infertility cases. Genetic abnormalities are major determinants particularly in severe and idiopathic forms, and include chromosomal abnormalities, copy number variations (CNVs), Y chromosome microdeletions and monogenic variants affecting spermatogenesis, sperm motility and morphology. However, at least 40% of all cases remain classified idiopathic. Recent advances in Next Generation Sequencing (NGS) technologies, including Clinical Exome Sequencing (CES), enabled the simultaneous analysis of thousands of genes, improving the understanding of its molecular basis. This study aims to expand knowledge of the genetic architecture of male infertility and identify novel candidate genes and molecular mechanisms involved in reproductive dysfunction through omics-based approaches, including Chromosomal Microarray Analysis (CMA) and NGS. Male patients undergoing In Vitro Fertilization (IVF) treatments were referred for advanced molecular and genomic investigations. An initial cohort of 160 male patients with idiopathic infertility, negative for CFTR testing and Y chromosome microdeletions, underwent conventional karyotyping, revealing chromosomal abnormalities and structural rearrangements in a subset, potentially associated with impaired spermatogenesis and reproductive dysfunction. CMA analysis is ongoing for patients with ambiguous karyotypes on GeneChip System 3000 (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). A cohort of 30 patients with severe phenotypes, despite negative prior genetic investigations, was selected for CES. NGS libraries will be prepared using a capture-based exome kit (ClinEX-4bases, 4bases SA, CH-6928 Manno, Switzerland), targeting coding regions and splice-site sequences. Libraries will be normalized, pooled and loaded onto a flow cell for sequencing on the Illumina NextSeq™ 550Dx platform. Genotype-phenotype analyses are currently in progress. Overall, these results may contribute to better defining the molecular signature of male infertility and optimizing prevention strategies.
Omics-driven insights into the genetic architecture of male infertility
Marisa Donato
;Fani Konstantinidou;Rosa Maria Fratini;Antonio Capalbo;Liborio Stuppia;
2026-01-01
Abstract
Male infertility is a multifactorial disorder affecting approximately 15% of couples worldwide and contributing to nearly 50% of infertility cases. Genetic abnormalities are major determinants particularly in severe and idiopathic forms, and include chromosomal abnormalities, copy number variations (CNVs), Y chromosome microdeletions and monogenic variants affecting spermatogenesis, sperm motility and morphology. However, at least 40% of all cases remain classified idiopathic. Recent advances in Next Generation Sequencing (NGS) technologies, including Clinical Exome Sequencing (CES), enabled the simultaneous analysis of thousands of genes, improving the understanding of its molecular basis. This study aims to expand knowledge of the genetic architecture of male infertility and identify novel candidate genes and molecular mechanisms involved in reproductive dysfunction through omics-based approaches, including Chromosomal Microarray Analysis (CMA) and NGS. Male patients undergoing In Vitro Fertilization (IVF) treatments were referred for advanced molecular and genomic investigations. An initial cohort of 160 male patients with idiopathic infertility, negative for CFTR testing and Y chromosome microdeletions, underwent conventional karyotyping, revealing chromosomal abnormalities and structural rearrangements in a subset, potentially associated with impaired spermatogenesis and reproductive dysfunction. CMA analysis is ongoing for patients with ambiguous karyotypes on GeneChip System 3000 (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). A cohort of 30 patients with severe phenotypes, despite negative prior genetic investigations, was selected for CES. NGS libraries will be prepared using a capture-based exome kit (ClinEX-4bases, 4bases SA, CH-6928 Manno, Switzerland), targeting coding regions and splice-site sequences. Libraries will be normalized, pooled and loaded onto a flow cell for sequencing on the Illumina NextSeq™ 550Dx platform. Genotype-phenotype analyses are currently in progress. Overall, these results may contribute to better defining the molecular signature of male infertility and optimizing prevention strategies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
