Genetic architecture of azoospermia—time to advance the standard of care
MJ Wyrwoll, N Köckerling, M Vockel, AK Dicke, N Rotte… - European urology, 2023 - Elsevier
MJ Wyrwoll, N Köckerling, M Vockel, AK Dicke, N Rotte, E Pohl, J Emich, M Wöste…
European urology, 2023•ElsevierBackground Crypto-and azoospermia (very few/no sperm in the semen) are main
contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF)
include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and
CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain
unexplained because monogenic causes are not analysed. Objective To elucidate the
monogenic contribution to azoospermia by prospective exome sequencing and strict …
contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF)
include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and
CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain
unexplained because monogenic causes are not analysed. Objective To elucidate the
monogenic contribution to azoospermia by prospective exome sequencing and strict …
Background
Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained because monogenic causes are not analysed.
Objective
To elucidate the monogenic contribution to azoospermia by prospective exome sequencing and strict application of recent clinical guidelines.
Design, setting, and participants
Since January 2017, we studied crypto- and azoospermic men without chromosomal aberrations and Y-chromosomal microdeletions attending the Centre of Reproductive Medicine and Andrology, Münster.
Outcome measurements and statistical analysis
We performed exome sequencing in 647 men, analysed 60 genes having at least previous limited clinical validity, and strictly assessed variants according to clinical guidelines.
Results and limitations
Overall, 55 patients (8.5%) with diagnostic genetic variants were identified. Of these patients, 20 (3.1%) carried mutations in CFTR or ADGRG2, and were diagnosed with OA. In 35 patients (5.4%) with SPGF, mutations in 20 different genes were identified. According to ClinGen criteria, 19 of the SPGF genes now reach at least moderate clinical validity. As limitations, only one transcript per gene was considered, and the list of genes is increasing rapidly so cannot be exhaustive.
Conclusions
The number of diagnostic genes in crypto-/azoospermia was almost doubled to 21 using exome-based analyses and clinical guidelines. Application of this procedure in routine diagnostics will significantly improve the diagnostic yield and clinical workup as the results indicate the success rate of testicular sperm extraction.
Patient summary
When no sperm are found in the semen, a man cannot conceive naturally. The causes are often unknown, but genetics play a major role. We searched for genetic variants in a large group of patients and found causal mutations for one in 12 men; these predict the chances for fatherhood.
Elsevier
