Undiagnosed RASopathies in infertile men

Area of Science:

• Genetics
• Endocrinology
• Reproductive Medicine

Background:

• RASopathies are congenital syndromes linked to the Ras/mitogen-activated protein kinase (MAPK) pathway, affecting approximately 1 in 1,000 individuals.
• Cryptorchidism (CR), a common feature in RASopathy patients, is associated with spermatogenic failure (SPGF), a leading cause of male infertility.
• The overlap suggests that men seeking infertility management may include undiagnosed RASopathy cases.

Purpose of the Study:

• To investigate the prevalence of likely pathogenic or pathogenic (LP/P) variants in RASopathy-associated genes among men with idiopathic spermatogenic failure.
• To determine if undiagnosed RASopathies contribute to male infertility, particularly in cases with a history of cryptorchidism.
• To assess the clinical presentation and associated health concerns in infertile men with identified RASopathy gene variants.

Main Methods:

• Exome sequencing was performed on 521 men with idiopathic SPGF (including 155 with CR) and 323 normozoospermic controls from the ESTonian ANDrology (ESTAND) cohort.
• RASopathy-specific variant interpretation guidelines were applied to assess pathogenicity.
• The findings were validated in the Genetics of Male Infertility Initiative (GEMINI) cohort, comprising 1,416 SPGF cases and 317 fertile men.

Main Results:

• LP/P variants in RASopathy-linked genes were identified in 3.9% of men with CR and SPGF, a significant enrichment compared to controls (0.3%).
• Overall, 17 subjects across both cohorts were diagnosed with undiagnosed RASopathies, primarily among SPGF patients (15 cases, 10 with CR).
• All affected individuals presented with congenital genitourinary anomalies, skeletal/joint conditions, and other RASopathy-related issues, including rare malignancies in four cases.

Conclusions:

• Congenital defects in Ras/MAPK pathway genes represent a novel genetic etiology for syndromic male infertility.
• Undiagnosed RASopathies are notably enriched in infertile men with a history of cryptorchidism.
• Infertile men diagnosed with RASopathies require comprehensive evaluation for associated congenital anomalies, skeletal conditions, and potential malignancies.