Abstract

A rare genetic condition, Kallmann syndrome (KS), causes congenital hypogonadotropic hypogonadism (CHH) and anosmia, resulting from impaired migration of gonadotropin-releasing hormone (GnRH) neurons. This developmental process is regulated by the semaphorin–neuropilin–plexin signaling pathway, in which SEMA3A interacts with neuropilin (NRP) co-receptors and plexin receptors (e.g., PLXNA1) to guide axonal navigation and GnRH neuron migration. This study aimed to review and synthesize current evidence on PLXNA1 variants and their role in oligogenic inheritance in KS. A literature search was conducted for studies related to PLXNA1 variants and oligogenic inheritance in KS. Studies focusing on GnRH neuron development, genotype-phenotype correlations, and clinical manifestations were included. This review highlights the disruption of the semaphorin–neuropilin–plexin signaling pathway in KS pathogenesis and reports missense variants in PLXNA1. Missense variants in PLXNA1 often affect the extracellular domain of PLXNA1, impairing its interaction within the SEMA3A–NRP–PLXNA1 receptor complex required for GnRH neuron migration. A total of 10 probands with predominantly missense PLXNA1 variants were identified, with co-occurring variants in other KS-associated genes (PROKR2, IGSF10, SOX10, NR0B1, OTUD4, and SPRY4) present in 6 out of 10 cases. These co-occurring variants suggest that disruption of the semaphorin–neuropilin–plexin pathway, in combination with additional genetic variants, may contribute to the variable clinical presentation of KS. Further studies are needed to clarify the functional impact of these variants and their role in disease pathogenesis.

Key words: Congenital hypogonadism, Oligogenicity, PLXNA1, Kallmann syndrome, Semaphorin signaling