Biallelic PAX6 Variants in an Adult With Severe Microphthalmia and Preserved Intellectual Function

PAX6 encodes a dosage-sensitive transcription factor that is essential for eye development. Heterozygous PAX6 disease is well characterized, but biallelic disease is extremely rare and has been associated with anophthalmia, severe brain malformations, and perinatal lethality. Here we report the first adult patient with biallelic pathogenic PAX6 variants and describe a novel phenotype that includes severe microphthalmia, anosmia, and autism spectrum disorder, Level 1. Notably, intellectual function was preserved. Genome sequencing revealed compound heterozygosity for the missense variant c.622C>T p.(Arg208Trp), inherited from the patient's mother diagnosed with sclerocornea and iris hypoplasia, and the nonsense variant c.718C>T p.(Arg240*), inherited from the patient's father diagnosed with aniridia. We compare the phenotype and genotype with previously reported biallelic patients and observe that the neurological phenotype of the patient fits the pattern observed in PAX6 haploinsufficiency. We propose that the severe microphthalmia is the result of haploinsufficiency and a hypomorphic, eye-restricted effect of the missense variant, which is predicted to affect the DNA-binding homeodomain of PAX6. Together, these findings expand the phenotypic spectrum of biallelic PAX6 disease and suggest that the homeodomain may have a tissue-specific role that is critical for eye development but largely dispensable for brain development.