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Nearly half of all cases of male infertility are thought to be associated with genetic defects.1–3 Up to 20% of infertile men receive a diagnosis of azoospermia.3 Nonobstructive azoospermia is spermatogenic failure that is defined by the absence of spermatozoa in the seminal fluid.1,4 Azoospermia is a heterogeneous condition with several histologic phenotypes.5 The most severe form of azoospermia is the Sertoli-cell–only syndrome, which is defined as a complete absence of germ cells.6,7
Azoospermia with meiotic arrest is a milder form of infertility with a cessation at the spermatocyte stage of germ-cell formation.7 Both the Sertoli-cell–only syndrome and meiotic arrest affect all seminiferous tubules. Mixed testicular atrophy is yet a milder form of azoospermia with a variable degree of germ-cell loss and spermatozoa detected in at least some tubules.1,7
Up to 20% of men with nonobstructive azoospermia have a detectable chromosomal abnormality; these abnormalities include sex-chromosome anomalies (e.g., Klinefelter’s syndrome), structural aberrations (e.g., translocations and inversions), and Y-chromosome microdeletions of azoospermia factors.8 However, the remaining 80% of men with nonobstructive azoospermia have negative results on genetic testing and receive a diagnosis of “idiopathic” azoospermia.3
Numerous mouse models that have linked hundreds of genes with azoospermia and infertility provide insight into the molecular mechanisms responsible for this condition in mice. The loss of function of these genes causes infertility.2 Yet, only a few studies involving humans with azoospermia have identified mutations in genes that are associated with infertility in mice (e.g., HSF2, SYCP3, PRM1, PRM2, SOHLH1, and NR5A1).9–13 This could be explained by the low discriminative power of a single candidate gene; hundreds of genes may contribute to the diagnosis of histologically diverse azoospermia.
We performed array comparative genomic hybridization (aCGH) in blood samples obtained from patients with azoospermia and mutation screening by means of direct Sanger sequencing of the testis-expressed 11 (TEX11) gene open reading frame in patients with azoospermia and controls.
Methods
Patients
The initial study cohort was composed of 49 men recruited from the Center for Fertility and Reproductive Endocrinology at Magee–Womens Hospital of the University of Pittsburgh Medical Center and the Institute of Human...