NR5A1 c.991-1G > C splice-site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance

Clin Endocrinol (Oxf). 2021 Apr;94(4):656-666. doi: 10.1111/cen.14381. Epub 2020 Dec 9.


Objective: The study aimed to identify the genetic basis of partial gonadal dysgenesis (PGD) in a non-consanguineous family from Estonia.

Patients: Cousins P (proband) 1 (12 years; 46,XY) and P2 (18 years; 46,XY) presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2. Their distant relative, P3 (30 years; 46,XY), presented bilateral cryptorchidism and cryptozoospermia.

Design: Exome sequencing was targeted to P1-P3 and five unaffected family members.

Results: P1-P2 were identified as heterozygous carriers of NR5A1 c.991-1G > C. NR5A1 encodes the steroidogenic factor-1 essential in gonadal development and specifically expressed in adrenal, spleen, pituitary and testes. Together with a previous PGD case from Belgium (Robevska et al 2018), c.991-1G > C represents the first recurrent NR5A1 splice-site mutation identified in patients. The majority of previous reports on NR5A1 mutation carriers have not included phenotype-genotype data of the family members. Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers of NR5A1 c.991-1G > C. The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2). For P3, the pedigree structure supported a distinct genetic cause. He carries a previously undescribed likely pathogenic variant SOS1 p.Y136H. SOS1, critical in Ras/MAPK signalling and foetal development, is a strong novel candidate gene for cryptorchidism.

Conclusions: Detailed genetic profiling facilitates counselling and clinical management of the probands, and supports unaffected mutation carriers in the family for their reproductive decision making.

Keywords: NR5A1; SOS1; exome sequencing; incomplete penetrance; partial gonadal dysgenesis; patient management; splice-site variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Variation, Population
  • Gonadal Dysgenesis, 46,XY* / genetics
  • Humans
  • Male
  • Mutation
  • Penetrance*
  • Steroidogenic Factor 1* / genetics
  • Testis


  • NR5A1 protein, human
  • Steroidogenic Factor 1