Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism

Abstract

Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.

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

“…SOS1 gain‐of‐function dominant missense variants alter Ras/MAPK signalling and account for a significant proportion of Noonan syndrome cases (NS, MIM: 610733) 34 . Known pathogenic variants in NS genes, including SOS1 , have been reported in isolated cryptorchidism cases without typical characteristics of NS 35 . Re‐assessment of the P3 medical history revealed repeated visits to a dermatologist due to multiple nevi across the body, and erythema on his face and chest.…”

“…In addition to reproductive phenotype, P3 had various forms of dermatological concerns that have been often noticed in SOS1 ‐related NS patients. Cryptorchidism and hypospermatogenesis are observed in 60%‐80% of male NS cases, 37 and patients with isolated cryptorchidism have been reported to carry known pathogenic SOS1 variants that have been identified in NS patients 35 . In addition, cryptorchid testis has been shown to display significantly reduced SOS1 gene expression 38 .…”

CAG and GGN repeat polymorphisms in the androgen receptor gene of a Chilean pediatric cohort with idiopathic inguinal cryptorchidism

“…Our study population included a subset of 109 boys consecutively selected from a previous cohort of 283 boys described by Rodríguez and co‐workers 23 . This subset included all patients who had undergone orchidopexy for isolated inguinal cryptorchidism at the San Borja Arriarán Clinical Hospital in Santiago, Chile from 2012 to 2017.…”

“…Serum testosterone, LH, FSH, AMH, and inhibin B were measured as previously described 23 . The control serum hormones were measured by Radioimmunoassay for testosterone, and by Immunoradiometric assay for FSH and LH.…”

“…Our study population included a subset of 109 boys consecutively selected from a previous cohort of 283 boys described by Rodríguez and co-workers. 23 This subset included all patients who had undergone is shown in Supplementary Table 1.…”