Does genetics in infertile men impact on the pregnancy outcome through assisted reproductive technology

A multi-institutional research team led by Central South University (CSU) and The Chinese University of Hong Kong (CUHK) has unveiled the most comprehensive genomic analysis to date of idiopathic male infertility in a Chinese cohort, and tied specific gene defects to assisted reproductive technology (ART) outcomes. The study, involving exome sequencing of 2,054 men who received a negative genetic finding from clinical genetic workup, and detailed follow-up of sperm retrieval and intracytoplasmic sperm injection (ICSI) pregnancies, expands the catalog of clinically significant variants and offers evidence-based guidance for fertility management.

Male infertility affects about 7% of men globally, yet over 60% of cases remain idiopathic, posing challenges for treatment decisions and potential transmission risks to offspring. The CSU–CUHK team systematically evaluated 219 established infertility genes and identified a genetic diagnosis in 10.6% of patients, rising to 11.4% after incorporating human cases newly found from this study to support model-organism evidence. Notably, diagnostic yield varied by clinical presentation, patients with oligozoospermia showing higher yields than those with non-obstructive azoospermia.

“By pairing large-scale genomic profiling with ART outcomes, we provide actionable insights that can inform whether to pursue testicular sperm retrieval, use donor sperm, or anticipate ICSI prognosis,” said Yue-Qiu Tan, PhD, corresponding author at Central South University. “This work supports integrating genetic testing into routine evaluation to personalize care for infertile men.”

Key findings

Genetic diagnosis and yield

• Among 2,054 idiopathic cases (negative karyotype and Y microdeletion screening), 217 received a genetic diagnosis across autosomal recessive and X-linked genes (10.6%). This rose to 235 (11.4%) when supported by natural human knockouts.
• Fifteen genes accounted for nearly half of diagnostic cases, with DNAH1, MEI1, and GCNA among the most prevalent.
• Thirteen genes with prior model-organism evidence contributed an additional 0.9% diagnostic yield.

ART management and outcomes

• In 905 NOA patients, sperm retrieval rates did not differ significantly between genetically diagnosed and undiagnosed groups.
• Across ART cycles, gene-specific patterns emerged: defects in some genes (e.g., DNAH1) were associated with lower live-birth rates, while others showed favorable pregnancy outcomes.
• Cases with loss-of-function in genes mediating meiotic progression (e.g., C12orf40) demonstrated that the presence of ejaculated sperm does not guarantee ICSI success, underscoring functional deficits.

“Patients and clinicians often face uncertain decisions about biopsy, ICSI, or using donor sperm,” said Zirui Dong, PhD, co‑corresponding author at CUHK. “Our gene-level prognosis data begin to clarify where success is more or less likely, helping set realistic expectations.”

Study design and resources

The team conducted exome sequencing and burden analyses, validated selected variants, and correlated gene defects with sperm retrieval and first ICSI-cycle outcomes. An online database, GeLIM (The Genomic Landscape of Infertile Males: https://gelim.zxxyyy.cn), has been developed to house diagnostic cases and associated ART management information for promoting data sharing and future replication.

Apart from the diagnostic findings and the correlation to the ART pregnancy outcomes, the team also discovered 41 novel genes potentially correlated to the infertility serving as the foundation for the mechanistic study in future.

Limitations include cohort composition biases, the focus on the first ART cycle with limited case numbers per gene, not adjusting female factors, and methodological constraints of exome sequencing that miss non-coding variants and epigenetic changes. The authors call for larger, multi-cycle, and multi-omic studies to refine prognostic estimates and uncover additional etiologies.

About Central South University and The Chinese University of Hong Kong

Central South University is home to the NHC Key Laboratory of Human Stem Cell and Reproductive Engineering and the Clinical Research Center for Reproduction and Genetics in Hunan, China.

The Chinese University of Hong Kong is a premier research institution in Asia, globally recognized for its pioneering advancements in innovative medicine. CUHK Medicine drives world-class breakthroughs in reproductive medicine, genomic medicine, and fertility preservation.