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Kallmann syndrome is an inherited deficiency of gonadotropin-releasing hormone (GnRH) characterized by hypogonadism with delayed or absent puberty and impaired olfaction. While mutations in several genes have been implicated, many patients lack a molecular diagnosis. Semaphorin 3E (SEMA3E) is a secreted axon guidance cue whose role in GnRH neuron development has been recently elucidated. Two independent studies report pathogenic SEMA3E variants in individuals with Kallmann syndrome (PMID:25985271; PMID:25985275). These findings extend the spectrum of neurotrophic genes associated with GnRH neuron migration and survival. Here, we summarize the clinical, genetic, and experimental evidence supporting SEMA3E as a causative gene for Kallmann syndrome.
In a pivotal report, Cariboni and colleagues identified a heterozygous point mutation in SEMA3E (c.1855C>T (p.Arg619Cys)) shared by two brothers presenting with Kallmann syndrome (PMID:25985275). Subsequent exome sequencing in a cohort of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism revealed an additional heterozygous missense variant affecting Pro323 in one Kallmann syndrome proband (PMID:37814704). Together, these studies report three affected individuals from two families harboring missense SEMA3E variants. No loss-of-function, splice, or structural variants in SEMA3E have been reported in Kallmann syndrome to date. Both identified missense changes localize to the Sema domain critical for receptor binding. The variant spectrum in Kallmann syndrome is thus limited to rare, conserved missense alleles.
Segregation analysis in the two brothers confirms inheritance of c.1855C>T by both affected sibs, but parental transmission data are lacking for the KS pedigrees. In silico tools (SIFT, PolyPhen-2) predict deleterious effects on protein stability and function (PMID:37814704). Absence of these variants from population databases further supports their rarity. The absence of additional family data limits formal segregation scoring. No recurrent or founder alleles beyond the sibling pair have been described. This restricted variant spectrum and incomplete segregation data underscore the need for further familial studies.
Functional assays demonstrate that recombinant wild-type SEMA3E protects maturing GnRH neurons from apoptosis via plexin D1 (PLXND1)-dependent activation of PI3K signaling (PMID:25985275). The p.Arg619Cys mutation abolishes this neurotrophic effect, resulting in increased GnRH neuron death in vitro. Knockout mice lacking Sema3e exhibit enhanced apoptosis of GnRH neurons during development, reduced innervation of the median eminence, and impaired testicular growth (PMID:25985271). These concordant cellular and animal models recapitulate key clinical features of Kallmann syndrome. Rescue experiments further confirm that SEMA3E function is necessary and sufficient for GnRH neuron survival. Hence, experimental data provide strong mechanistic support for SEMA3E pathogenicity in KS.
The collective evidence supports a model in which heterozygous SEMA3E missense variants disrupt neurotrophic signaling, leading to GnRH neuron deficiency and the KS phenotype. This mechanism is consistent with haploinsufficiency rather than complete loss of function. Autosomal dominant inheritance with variable penetrance is suggested by familial presentations and absence of biallelic cases. The semaphorin–plexin axis emerges as a critical pathway for GnRH neuron migration and survival in humans. Interaction with other KS-associated genes such as PLXND1 implies possible oligogenic contributions. Future studies should explore additional SEMA3E mutations and modifiers across diverse populations.
In summary, three probands from two families carrying heterozygous SEMA3E missense variants demonstrate genetic association with Kallmann syndrome. Functional data from cellular and murine models confirm that mutant SEMA3E fails to support GnRH neuron survival, fulfilling experimental criteria for pathogenicity. According to ClinGen, the current evidence supports a Moderate gene–disease validity classification. Inclusion of SEMA3E in diagnostic gene panels will enhance molecular diagnosis for KS patients. Genetic counseling should consider variable expressivity and incomplete penetrance. Key take-home: Heterozygous missense variants in SEMA3E disrupt semaphorin signaling and underlie a subset of Kallmann syndrome, informing both patient care and research.
Gene–Disease AssociationModerate3 probands (2 siblings and 1 sporadic), limited segregation but consistent findings across two studies and functional concordance Genetic EvidenceModerate3 probands across 2 families with rare missense SEMA3E variants identified by exome sequencing [PMID:25985275; PMID:37814704] Functional EvidenceModerateMurine Sema3e knockout recapitulates GnRH neuron deficiency and mutant SEMA3E fails rescue in neuron survival assays [PMID:25985275] |