Novel compound heterozygous variants in SIX6 cause a PAX2 like Dysplastic Optic Disc with macular abnormalities...

Congenital optic disc dysplasia with coexistent macular abnormalities is seen in Morning-glory disc anomaly, optic disc pit, PAX6-related disc coloboma, and in the PAX2-related Papillo-renal syndrome. We report novel compound heterozygous variants in SIX6 causing optic disc dysplasia and macular abnormality without coexisting cataract or microphthalmia for the first time in Chinese ethnicity and also describe the macular OCT findings.

A 4 year-8 months-old female child presented with poor vision, photophobia, and nystagmus noticed 4 months after her birth was diagnosed elsewhere to have isolated cone dystrophy. She was evaluated subsequently by an ocular geneticist. She underwent a complete ophthalmic evaluation including orthoptic evaluation, cycloplegic refraction, and a dilated fundus evaluation. She had fundus photography, macular OCT, and ERG. She had systemic evaluations, relevant systemic investigations, and molecular genetic testing.

Whole Exome Sequencing (WES) revealed compound heterozygous variants both in the SIX6 and in the TULP1 gene. No pathogenic variants were identified in the PAX2, PAX6 or in any of the other developmental genes or in the genes currently known to cause cone dystrophy or cone-rod dystrophy. Parents were heterozygous for variants in both SIX6 and TULP1.

Homozygous or compound heterozygous pathogenic variants in SIX6 can cause a dysplastic optic disc and coexistent macular abnormalities. This dysplastic disc may be clinically indistinguishable from that seen in the PAX2 related Papillo-renal syndrome. Careful optic disc evaluation of subtle disc dysplasia is critical in differentiating this extremely rare entity from other relatively common causes of isolated cone dystrophies or cone-rod dystrophies.