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Novel Genetic Alterations in Hypospadias
Jeffrey Villanueva, MD1, Mary Killian, M.D.1, Oluwaseun Orikogbo, B.A.2, Svetlana Yatsenko, M.D.3, Francis Schneck, M.D.1.
1Children's Hospital of Pittsburgh, Pittsburgh, PA, USA, 2University of Pittsburgh Medical School, Pittsburgh, PA, USA, 3Pittsburgh Cytogenetics Lab, Pittsburgh, PA, USA.

BACKGROUND: Hypospadias is a relatively common congenital anomaly affecting male urogenital development. Current research suggests that hypospadias is an etiologically heterogeneous condition likely explained by polygenic and complex trait models, where genetics and environment contribute to the development of this disease state. Most sporadic cases of hypospadias have an uncertain etiology, while disease-causing chromosomal loci have yet to be discovered. Describing novel genetic alterations associated with hypospadias adds to our understanding of its etiology and expected associated anomalies.
METHODS: IRB approval was obtained for a retrospective chart review of male patients with a diagnosis of hypospadias who had undergone genetic testing at our institution. Children are typically screened if they have multiple associated congenital issues. Peripheral blood was analyzed using G-banding chromosome analysis, whole genome and high-resolution X chromosome-specific microarrays. Patient charts were also reviewed for severity of hypospadias, surgical history, associated congenital anomalies, family history of genitourinary (GU) anomalies, and whether or not the patient was a product of in vitro fertilization (IVF).
RESULTS: A total of 13 boys with a hypospadias were screened for genetic anomalies. Four patients were found to have genetic aberrations. This included three patients with X chromosomal abnormalities detected by comparative genomic hybridization microarray and an additional patient with partial trisomy for the 9q33.1q43.13 region. The remaining nine patients had normal chromosome and microarray studies.
Meatal locations were as follows: 4 glanular, 4 coronal, 2 penile shaft, 3 scrotal/penoscrotal. Of those with penoscrotal hypospadias, 2/4 were found to have a genetic anomaly (PH-1 and PH-4). Eight boys underwent a hypospadias repair, with an average of 1.6 surgeries. 2 boys received a planned two staged repair. Notably, one child in the cohort ( PH-1) required 3 additional unplanned corrective surgeries after a single stage hypospadias repair. This patient is the only one in this cohort to have sustained an unexpected surgery, and had a personal and family history of suspected Ehlers-Danlos syndrome of undetermined etiology. Testes were descended in 10/13. In patient PH-4, both testes were nonpalpable. Two additional patients with negative genetic testing had abnormal positioning of the testes: one had bilateral suprascrotal testes and another had a unilateral suprascrotal testis. There was no family history of GU anomalies and none were the result of IVF.
CONCLUSIONS: Chromosomal aberrations were detected in 4/13 (30.7%) patients in our cohort, including submicroscopic genetic abnormalities in 3/4 patients. Interestingly, the X chromosome microdeletions and microduplications were present in three patients. Pathogenic sequence variants in the MAMLD1 gene were reported previously, however our patients represent the first case with pathogenic deletion. This study is limited by its retrospective nature and sample size. However, it describes 3 genetic abnormalities not previously associated with hypospadias. This may both improve our understanding of developmental defects leading to hypospadias and provide more accurate counseling to families.

Characteristics of the Identified Genetic Alterations Associated with Hypospadias
PatientChromosome Region (reference genome hg19)AlterationGene/Condition
PH-1chrX:149312270_149595626DeletionMAMLD1
PH-2chr22:18894,835-21505417
chrX:152170338-152562323
Deletion
Deletion
DiGeorge syndrome
PNMA3, PNMA6D, PNMA6C, MAGEA1
PH-3chr9:121634630_134419173DuplicationNR5A1, multiple
PH-4chrX:53,559,732-53,588,589DuplicationHUWE


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