Patients with OTX2 mutations have highly variable phenotypes, as the transcription factor is key in the development of retinal, pituitary gland, inner ear, and craniofacial structures. There are two recognized syndromes caused by OTX2 mutations: syndromic microphthalmia type 5 (MCOPS5), and combined pituitary hormone deficiency type 6 (CPHD6).

Anophthalmia/microphthalmia/coloboma (MAC) spectrum encompasses the most severe malformations of the eye. Together, they have an incidence of 2 in 10,000 births and can be unilateral or bilateral. These disorders are genetically heterogeneous. We ascertained a large three-generation family with multiple members showing variable phenotypes of syndromic microphthalmia. Exome sequencing was performed for the proband and his affected maternal aunt. Targeted sequencing of OTX2 gene was performed for other family members. Variable clinical presentation in the form of unilateral microphthalmia and bilateral microphthalmia as well as nonpenetrance were noted. Exome sequencing revealed a novel heterozygous variant c.278G>T (p.W93L) in OTX2 in the proband. All affected members as well as the unaffected mother of the proband carried the same variant. Syndromic microphthalmia due to mutations in OTX2 can present with significant intrafamilial phenotypic variability.