MON-059 - Heterozygous SOX2 Mutations in Central Hypogonadotropic Hypogonadism: Evidence from A Prenatal and A Postnatal Case with Bioinformatic Analyses

Background
The SOX2 gene encodes a key transcription factor essential for early embryonic development and hypothalamic–pituitary axis formation. Pathogenic SOX2 variants are a recognised cause of central hypogonadotropic hypogonadism (HH), typically presenting with micropenis and cryptorchidism. However, the molecular mechanisms by which heterozygous loss-of-function variants in SOX2 disrupt central reproductive axis development remain incompletely understood.

Methods
Two unrelated male patients presenting with micropenis and cryptorchidism were identified. In one patient, a prenatal diagnosis was established by amniocentesis, while the other was diagnosed postnatally. Genetic variants were identified by sequencing and evaluated using in silico pathogenicity prediction tools. Publicly available transcriptomic datasets and onine database were analysed to investigate the spatiotemporal expression pattern of SOX2 during human development. In addition, a protein–protein interaction (PPI) network was constructed, followed by Gene Ontology (GO) and KEGG pathway enrichment analyses, to explore SOX2-associated biological functions and signalling pathways.

Results
Both patients harboured heterozygous frameshift variants in SOX2. The prenatally diagnosed patient carried a de novo variant (c.606delG, p.S203Afs8), while the postnatally diagnosed patient carried a distinct heterozygous variant (c.70_89delAAG, p.N24Rfs65). Both variants were predicted to be deleterious by multiple in silico tools.
Spatiotemporal expression analysis demonstrated that SOX2 is highly expressed in the developing brain, particularly in the cerebral cortex and hypothalamus, with peak expression at the blastocyst stage and before 15 post-conception weeks (pcw), followed by a secondary increase during early infancy. The PPI network comprised 101 nodes and 1,574 interactions, with a highly significant network P value ( < 1.0 × 10⁻¹⁶). Functional enrichment analyses revealed that SOX2-interacting genes were significantly involved in cell fate determination, stem cell population maintenance, and transcriptional regulation, with enrichment in pathways regulating pluripotency of stem cells, Hippo signalling, and TGF-β signalling.

Conclusion
Consistent with the established role of SOX2 in central hypogonadotropic hypogonadism, this study provides integrated clinical and bioinformatic evidence supporting SOX2 haploinsufficiency as a key mechanism underlying impaired hypothalamic–pituitary development. Rather than expanding the phenotypic spectrum, our findings strengthen the mechanistic framework linking heterozygous SOX2 loss-of-function variants to central reproductive axis dysfunction, supporting its inclusion in the genetic evaluation and counselling of patients with micropenis and cryptorchidism.

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