Identifying infrequent genetic changes in monozygotic twins afflicted with hypospadias via targeted panel sequencing.

Purpose: We aimed to identify the genetic causes of hypospadias in children using targeted gene panel sequencing for disorders of sex development (DSD).

Materials and methods: This study included 18 twin boys with hypospadias: seven and two pairs were monozygotic and dizygotic twins, respectively, and six were discordant and three were concordant twins. Targeted gene panel sequencing for 67 known DSD genes was performed. Sequence variants were classified into five different categories, pathogenic, likely pathogenic, variants of uncertain significance, likely benign, and benign, following the American College of Medical Genetics and Genomics Standards and Guidelines.

Results: The mean gestational age and birth weight were 35.3±2.0 weeks and 1.96±0.61 kg, respectively, with seven patients being small for gestational age. Hypospadias was present in 12 patients, with posterior type in 33.3% and anterior type in 66.7%. In three families with twins, both siblings had hypospadias. In addition, cryptorchidism was observed in one subject. Surgical correction of hypospadias was performed at a mean age of 22.1 months. Molecular analysis identified 12 different genetic variants, including two pathogenic mutations in the AMH (p.E389*) and SRD5A2 (p.R246Q) genes, found in subjects with hypospadias, respectively. However, only heterozygous mutations were detected.

Conclusions: This study did not identify a definitive genetic component contributing to the development of hypospadias; however, the findings suggest that intrauterine growth retardation may play a significant role.