Genitourinary Defects Associated with Genomic Deletions in 2p15 Encompassing OTX1

Abstract

Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1–4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2–7 had large de novo CNVs (2.39–6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.

Characteristics of 2p15‐p16.1 microdeletion syndrome: Review and description of two additional patients

“…Red bars, blue bars, and gray bars indicate the deletion regions identified in the present study, previous studies, and a study by J orgez et al. (), respectively. The shaded gray bars indicate the deletions identified in patients with facial features typical of 2p15‐p16.1 microdeletion syndrome.…”

“…Whereas the parental origins of the deletions in patient 2 in this study and in patients #1 and #2 in the study by J orgez et al. () were not examined, the de novo origin of all other deletions was confirmed.…”

GnRHa Treatment of Cryptorchid Boys Affects Genes Involved in Hormonal Control of the HPG Axis and Fertility

“…While no role has been found for it, deletion of its sense gene OTX1 was found in 6 subjects with genitourinary defects. Three of these individuals were diagnosed with cryptorchidism [Jorgez et al, 2014]. Moreover, Otx2 heterozygous male mice display compromised fertility (reduced LH levels and testicular weight) due to a defect in the development, number, and migration of GnRH neurons [Larder et al, 2013].…”

Is Hormonal Treatment of Congenital Undescended Testes Justified A Debate

“…Furthermore, deletion of OTX1 was found in 6 subjects with genitourinary defects. Three of these individuals were diagnosed with cryptorchidism [Jorgez et al, 2014]. Otx2 heterozygous male mice display compromised fertility (reduced LH levels and testicular weight) due to a defect in the development, number, and migration of GnRH neurons [Larder et al, 2013].…”