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.
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.
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.
Júlia Martinková, Michaela Mihulová, Miroslava Balaščáková et al.· Frontiers in Pediatrics· 0 citations
BACKGROUND
Complete androgen insensitivity syndrome (CAIS) is one of the most prevalent conditions of disorders/differences of sex development (DSD), with an X-linked recessive inheritance. A hemizygous pathogenic variant in the AR gene causes the condition.
CASE REPORT
We present a five-generation Czech family with several CAIS-positive relatives. The proband is a 27-year-old female patient with a 46,XY karyotype, who exhibits the typical CAIS phenotype. This includes female external genitalia, the absence of uterus, a blind-ending vagina, undescended testes, and almost missing axillary and pubic hair.
METHODS AND RESULTS
We identified a novel pathogenic, hemizygous NM_000044.4(AR):c.-66_220del p.? variant using Sanger DNA sequencing with specifically designed primers. This AR deletion was 286 bp in length and initiated in the 5'-UTR, terminating within the polymorphic CAG repeats in exon 1 of the AR gene. The AR variant removed the original initiation codon ATG, resulting in a shortened AR transcript with an unknown effect on the translation.
CONCLUSION
We describe a unique AR deletion identified in a 46,XY female patient with CAIS. The variant segregates in the large CAIS family; it was detected in five affected relatives, while the four remaining family members were asymptomatic carriers.
Júlia Martinková, Andrea Gřegořová, M. Wayhelova et al.· Biomedical papers of the Med...· 0 citations
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