Abstract

Abstract Background Current guidelines indicate that patients with extreme oligozoospermia or azoospermia should be tested for chromosomal imbalances, azoospermia factor (AZF) deletions and/or CFTR variants. For other sperm abnormalities, no genetic diagnostics are recommended. Objectives To determine whether exome sequencing (ES) with combined copy number variant (CNV) and single nucleotide variant (SNV) analysis is a reliable first‐tier method to replace current methods (validation study), and to evaluate the diagnostic yield after 10 months of implementation (evaluation study). Materials and Methods In the validation study, ES was performed on DNA of patients already diagnosed with AZF deletions ( n = 17), (non‐)mosaic sex chromosomal aneuploidies or structural chromosomal anomalies ( n = 37), CFTR variants ( n = 26), or variants in known infertility genes ( n = 4), and 90 controls. The data were analyzed using our standard diagnostic pipeline, with a bioinformatic filter for 130 male infertility genes. In the evaluation study, results of 292 clinical exomes were included. Results All previously reported variants in the validation cohort, including clinically relevant Y‐chromosomal microdeletions, were correctly identified and reliably detected. In the evaluation study, we identified one or more clinically relevant genetic anomalies in 67 of 292 of all cases (22.9%): these included aberrations that could have been detected with current methods in 30 of 67 patients (10.2% of total), (possible) (mono)genetic causes in the male infertility gene panel in 28 of 67 patients (9.6%), and carriership of cystic fibrosis in nine of 67 patients (3.1%). Conclusion ES is a reliable first‐tier method to detect the most common genetic causes of male infertility and, as additional genetic causes can be detected, in our evaluation cohort the diagnostic yield almost doubled (10.2%–19.8%, excluding CF carriers). A genetic diagnosis provides answers on the cause of infertility and helps the professionals in the counseling for treatment, possible co‐morbidities and risk for offspring and/or family members. Karyotyping will still remain necessary for detecting balanced translocations or low‐grade chromosomal mosaicism.