Significantly increased load of hereditary cancer-linked germline variants in infertile men.

Study Question: What is the load and profile of hereditary cancer-linked germline variants in infertile compared to fertile men?

Summary Answer: This study showed almost 5-fold enrichment of disease-causing findings in hereditary cancer genes in infertile compared to fertile men (6.9% vs 1.5%, =2.

Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies.