Father and son with a pathogenic variant c.614dup p.(Gln206Thrfs*20) in the NR5A1 gene: a case report

Background Steroidogenic factor 1 (SF-1), encoded by the NR5A1 gene, is a critical transcriptional regulator of adrenal and gonadal development. Pathogenic NR5A1 variants lead to a broad phenotypic spectrum characterized by insufficient virilization, including gonadal and testicular dysgenesis, ambiguous genitalia, hypospadias, micropenis, cryptorchidism, anorchia, and male infertility. This case report characterizes the clinical and genetic findings in a boy and his father with differences of sex development (DSD) caused by a heterozygous NR5A1 frameshift variant, thereby expanding our understanding of phenotypic mechanisms, paternal inheritance, and reproductive potential in this disorder. Case presentation We report a unique case of a Czech family in which a father and his son exhibited a 46,XY karyotype, genital malformations, and palpable testes. Exome sequencing identified the heterozygous frameshift variant, c.614dup p.(Gln206Thrfs*20), in the NR5A1 gene in both individuals. This rare NR5A1 variant had previously been reported only in 46,XY female patients with DSD. Conclusion Here, we present the first report of paternal transmission of the pathogenic NM_004959.5(NR5A1):c.614dup p.(Gln206Thrfs*20) variant to an affected son. Despite the associated genital malformation and the genetic variant, the father achieved successful reproduction via in vitro fertilization.