Examination of SOX2 in variable ocular conditions identifies a recurrent deletion in microphthalmia and lack of mutations in other phenotypes

Purpose The role of SRY-Box 2 (SOX2) in anophthalmia/microphthalmia (A/M) is well known, with 10%–20% of A/M explained by mutations in SOX2. SOX2 plays roles in the development of both the posterior and anterior segment structures of the eye and relies on interactions with tissue-specific partner proteins to execute its function, raising the possibility that SOX2 mutations may result in varying ocular phenotypes. Recent data has identified a missense mutation in SOX2 in an extended pedigree with phenotypes as varied as A/M, isolated iris hypoplasia, iris and chorioretinal coloboma, pupil defects, and hypermetropia, suggesting a broader phenotypic spectrum associated with SOX2 mutations. Methods Screening of SOX2 was completed in 89 patients with a variety of ocular anomalies, including 28 with A/M and 61 with normal eye size and anterior segment dysgenesis (28), cataract (14), isolated coloboma (5), or other eye disorders (14). Results The recurrent de novo frameshift mutation c.70del20 was identified in one patient with microphthalmia and syndromic anomalies consistent with SOX2 anophthalmia syndrome; the mutation frequency in our A/M population (4%) was lower than previously reported; it is likely that extensive utilization of clinical SOX2 testing has led to a bias toward SOX2-negative A/M cases in our research cohort. No disease-causing mutations were identified in patients with non-microphthalmia phenotypes. Conclusions The recurrent c.70del20 mutation accounts for 21% of all independent SOX2 mutations reported to date. Due to the increased use of clinical SOX2 testing, the frequency of SOX2 mutations identified in research A/M populations will likely continue to decrease. Mutations in SOX2 do not appear to be a common cause of ocular defects other than anophthalmia/microphthalmia.