Bilateral Testicular Regression Syndrome and Optic Nerve Atrophy: Clinical Aspects of a Child with a <italic>SEMA3E</italic> Loss-of-Function Variant

Abstract – Introduction: SEMA3E is a secreted class 3 semaphorin that, in mice, plays roles in neuronal guidance, cardiovascular morphogenesis, angiogenesis, and vascular homeostasis. Adult male mice lacking SEMA3E exhibit reduced testicular size compared to wild-type littermates, indicating a potential role in reproductive function. In humans, heterozygous missense variants in SEMA3E were initially reported to be associated with CHARGE syndrome and hypogonadotropic hypogonadism with anosmia. However, these associations have since been questioned, and the contribution of SEMA3E variants to human disease is unclear. Methods: We describe the results of exome sequencing of a 46, XY boy with unexplained bilateral testicular regression syndrome and optic nerve atrophy. Results: Exome sequencing indicates that he carries a heterozygous frameshift variant (c.942del, p.Leu314PheTer11) in the SEMA3E gene. The variant is located within the functional SEMA domain of the protein and is predicted to trigger nonsense-mediated mRNA decay. This is the second reported loss-of-function (LoF) variant in the highly conserved SEMA3E gene. A previously described LoF variant was identified in a child presenting with severe intellectual disability and cognitive regression. Conclusion: LoF SEMA3E variants may be associated with a broad and variable spectrum of clinical phenotypes.