Deletion of and on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.

Background: Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated.

Methods: Here, we report on genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members and compared to normal controls to identify dysregulated genes due to this deletion.

Results: Our patient's Xq28 deletion is 44,806 bp and contains only two genes, and . Expression of both and are completely abolished in the patient. Gene ontology analyses of differentially expressed genes (DEGs) in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier (SCB) regulation, apoptosis, inflammatory response, and gonadotropin-releasing regulation. Indeed, our patient has an elevated follicle stimulating hormone (FSH) level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation (XCI) is skewed toward the deleted X, suggesting a mechanism to avoid FSH dysregulation.

Conclusion: Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that loss of function of and results in dysregulation of apoptosis, inflammation, and FSH, and is sufficient to cause Xq28-associated HH.