Low frequency of pathogenic allelic variants in the 46,XY differences of sex development (DSD)-related genes in small for gestational age children with hypospadias

Background Hypospadias is a congenital disorder of male genital formation where the urinary opening is not on the head of the penis and genetic factors play an important role in the incidence of this early developmental defect in 46,XY individuals, in both isolated and syndromic forms. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology, ranging from 15 to 30%, but the detection of hypospadias’ etiology remains low. Patients and methods from a cohort of 46,XY DSD patients, we identified 25 SGA children with medium or proximal hypospadias; four of them with associated syndromic characteristics. DNA samples from subjects were studied by massively parallel targeted sequencing (MPTS) using a targeted panel. MLPA was used for molecular diagnosis in two children with clinical phenotype of Silver Russel syndrome. Results Loss of DNA methylation (11p15 LOM) at ICR1 was identified in two out of four syndromic children. The other syndromic patient had 3M syndrome phenotype and two novel likely-pathogenic variants in compound heterozygous state were found in CUL7 gene. The last syndromic subject had Mulibrey nanism and, a homozygous variant in TRIM37 was identified in the patient and confirmed in heterozygous state in the mother. Among non-syndromic children seven rare heterozygous variants with uncertain significance in six DSD-related genes were identified: two children had DHX37 variants associated with GATA4 and WWOX variants, respectively; three children had heterozygous variants, in WT1, IGF1R , and BMP8B genes. Conclusion Pathogenic or likely-pathogenic variants in DSD-related genes were not identified in non-syndromic SGA children with hypospadias, suggesting that multi-factorial causes, unknown genes or unidentified environmental factors (epigenetic defects), may be involved in the etiology of this condition.