Diverse SOX3 genetic variants and their associated phenotypic spectrum in human disease

SOX3 is a single-exon gene located on the X chromosome (Xq27.1), encoding a transcription factor critical for early central nervous system and pituitary development, as well as gonadal function. A growing body of literature reports a diverse array of phenotypes associated with different classes of SOX3 variants, including single nucleotide variants, indels, polyalanine tract changes, copy number variants, and structural rearrangements. These variants have been implicated in conditions ranging from pan-hypopituitarism or isolated growth hormone deficiency to neural tube defects, disorders/differences in sex development, and complex syndromes involving craniofacial and intellectual disability. In this review, we comprehensively summarize all known variants involving SOX3 reported to date, highlighting the different pathogenetic mechanisms that have been reported or hypothesized (e.g., gene dosage, transcriptional regulation) and the phenotypes to which these variants are associated to. Special emphasis is placed on established genotype-phenotype correlations and the challenges in interpretation relevant to clinical diagnostics. This review aims to provide a reference framework for clinicians, researchers, and geneticists working with SOX3-related disorders.