Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.
Human genetics. 2022 Dec 16 [Epub ahead of print]
Zirui Dong, Jicheng Qian, Tracy Sze Man Law, Matthew Hoi Kin Chau, Ye Cao, Shuwen Xue, Steve Tong, Yilin Zhao, Yvonne K Kwok, Karen Ng, David Yiu Leung Chan, Peter K-F Chiu, Chi-Fai Ng, Cathy Hoi Sze Chung, Jennifer Sze Man Mak, Tak Yeung Leung, Jacqueline Pui Wah Chung, Cynthia C Morton, Kwong Wai Choy
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China. ., Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China., SH Ho Urology Centre, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China., Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, 02115, USA., Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China. .