SOX2 pathogenic variants with normal eyes: Expanding the phenotypic spectrum

SOX2 pathogenic variants, though rare, constitute the most commonly known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation, but with multi-system developmental disorders, have been reported, suggesting that the range of clinical phenotypes is broader than previously appreciated. We detail two patients with bilateral structurally normal eyes along with 11 other previously published patients. Our findings suggest that there is no obvious phenotypic or genotypic pattern that may help set apart patients with normal eyes. Our patients provide further evidence for broadening the phenotypic spectrum of SOX2 mutations and re-appraising the designation of SOX2 disorder as an anophthalmia/microphthalmia syndrome. We emphasize the importance of considering SOX2 pathogenic variants in the differential diagnoses of individuals with normal eyes, who may have varying combinations of features such as developmental delay, urogenital abnormalities, gastro-intestinal anomalies, pituitary dysfunction, midline structural anomalies, and complex movement disorders, seizures or other neurological issues.

Automated summary

SOX2 pathogenic variants are the most common known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation but with multi-system developmental disorders have been reported, indicating a broader range of clinical phenotypes. Our study suggests that there is no discernible pattern to distinguish patients with normal eyes. Our findings further expand the phenotypic spectrum of SOX2 mutations and challenge the classification of SOX2 disorder as solely an anophthalmia/microphthalmia syndrome. Considering SOX2 pathogenic variants in individuals with normal eyes is important for differential diagnoses, given the various combinations of features associated with this condition.