OTX2 pathogenic variants have been associated with various clinical features.
The main phenotype associated with OTX2 mutations consists in eye growth defects such as microphthalmia and anophthalmia (M/A). The prevalence of M/A is around 1 per 10.000 birth and OTX2 is the second most frequently involved gene (3%) after the major gene SOX2. OTX2 pathogenic variants have also been described in some patients with retinal dystrophies.
The second most common feature observed in patients with OTX2 pathogenic variations is hypopituitarism due to developmental defects of the pituitary gland, often responsible for short stature.
The craniofacial structures are also frequently affected with abnormalities involving the ears, mouth and mandible (first branchial arch). OTX2 pathogenic variations have been described in Agnathia-otocephaly complex as well as in the OAV (Oculo-Auricular-vertebral) spectrum.
Each of these malformative features can be isolated but a combination of defects can sometimes be observed within the same patient (e.g: microphthalmia and hypopituitarism or microphthalmia and mandibular defects). Beyond this variable expressivity, there is a wide allelic heterogeneity described for the mutations in this gene with both Single Nucleotide Variant (SNV) (missense and truncating) and Copy Number Variant (CNV) (deletions and duplications) reported. OTX2 mutations are dominantly inherited and incomplete penetrance and germinal mosaicism have been described.
Although no genotype-phenotype correlation clearly explains the wide phenotypic spectrum observed within or between mutated families, it is important to note that the OTX2 microduplications have been reported in OAV phenotype
OTX2