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

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.

Automated summary

This study identified the genetic basis of partial gonadal dysgenesis (PGD) in a non-consanguineous family from Estonia, with some patients carrying the NR5A1 c.991-1G > C mutation. Segregation analysis showed incomplete penetrance and phenotypic variability among carriers of this mutation, with possible modulation by rare heterozygous variants inherited from the other parent. The study also identified a likely pathogenic variant SOS1 p.Y136H in another patient, supporting a distinct genetic cause for their condition.