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

Tijdschriftbijdrage - Tijdschriftartikel

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.

Tijdschrift: Clinical Endocrinology
ISSN: 0300-0664
Issue: 4
Volume: 94
Pagina's: 656-666
Aantal pagina's: 11
Jaar van publicatie:2021
  • WoS Id: 000596698200001
  • ORCID: /0000-0002-4339-2791/work/92172073
  • Scopus Id: 85097288366
  • ORCID: /0000-0003-3645-1455/work/90944000
  • DOI: https://doi.org/10.1111/cen.14381