Maris Laan1, Laura Kasak1, Kęstutis Timinskas2, Marina Grigorova1, Česlovas Venclovas2, Alexandre Renaux3,4,5, Tom Lenaerts3,4,5, Margus Punab6,7. 1. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. 2. Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania. 3. Interuniversity Institute of Bioinformatics in Brussels, Université libre de Bruxelles, Vrije Universiteit Brussel, Brussels, Belgium. 4. Machine Learning Group, Université libre de Bruxelles, Brussels, Belgium. 5. Artificial Intelligence lab, Vrije Universiteit Brussel, Brussels, Belgium. 6. Andrology Center, Tartu University Hospital, Tartu, Estonia. 7. Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Abstract
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.
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 PROP1c.301_302delAG (P2). For P3, the pedigree structure supported a distinct genetic cause. He carries a previously undescribed likely pathogenic variant SOS1p.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.
Authors: Charlotte Nachtegael; Barbara Gravel; Arnau Dillen; Guillaume Smits; Ann Nowé; Sofia Papadimitriou; Tom Lenaerts Journal: Database (Oxford) Date: 2022-04-12 Impact factor: 4.462