Long-read sequencing for comprehensive genomic profiling of infertile men
Abstract Our study employs long-read sequencing technology on the Oxford Nanopore PromethION device to identify genomic variants associated with male infertility, enhancing the detection capabilities beyond what short-read sequencing achieves. We sequenced the genomes of over 100 men with different infertility issues at coverages exceeding 40x, using the T2T-CHM13v2.0 assembly for precise Y-chromosome analysis. Our methodologies allowed us to identify clinically relevant variants potentially linked to observed infertility phenotypes. Key discoveries include several patients with pathogenic variants impacting hormone levels, sperm motility, spermiogenesis, and sperm-egg interaction — such as a novel homozygous variant in the LHB gene related to azoospermia and lack of puberty, and rare pathogenic variants in the DNAH2, TDRD6, TEX14, and PRSS55 genes linked to various sperm dysfunctions. These findings underscore the utility of long-read sequencing in revealing complex genetic factors underlying male infertility, offering new insights, and enhancing genetic diagnosis and treatment approaches. This research advances our understanding of the genetic architecture of infertility and supports personalized medicine initiatives in reproductive health. Biography Thomas X. Garcia, PhD, HCLD, is Assistant Professor and Clinical Laboratory Director at Baylor College of Medicine, USA, with appointments in the Departments of Urology and Pathology & Immunology. Dr. Garcia directs several specialized research and clinical laboratories, and spearheads research aimed at elucidating novel mechanisms underlying sperm development and function. His work involves advanced genome sequencing and the creation of knockout mouse models. Thomas has identified numerous genes previously unlinked to male infertility and has developed a searchable database, MRGDv2, to aid research. Additionally, he contributes to the scientific community as journal and NIH study section reviewer.