Abstract
Purpose :
The PAX6 gene is the master control gene of eye development. Mutations involving PAX6 result in a spectrum of ocular phenotypes including isolated aniridia, Peters’ anomaly, juvenile cataract, microphthalmia, ocular coloboma, nystagmus, optic nerve hypoplasia, and isolated foveal hypoplasia. Patients with molecularly confirmed heterozygous PAX6 mutations mostly show complete penetrance, there is a suggested genotype-phenotype correlation with missense variants, particularly those located in the paired box domain, tend to result in atypical/milder or variable-phenotype with more residual iris tissue and a lower frequency of sight reducing features. Here we report a family with a PAX6 heterozygous missense mutation displaying non-penetrance.
Methods :
A 23-year old female patient presented with nystagmus from age 6 months. Her parents were unaffected, her paternal grandmother reported glaucoma. The patient underwent genetic testing through a clinical exome and a PAX6 heterozygous missense mutation was detected c.214G>C p.(Gly72Arg) in the paired box domain. The unaffected father was found to carry the same pathogenic variant but grandmother was normal. Full phenotypic assessment with ophthalmic examination, eye-movement recordings, AS-OCT, SD-OCT, visual fields and electrophysiology was undertaken in proband and father to confirm non-penetrance.
Results :
The proband had a best corrected visual acuity (BCVA) of OD 1.00 and OS 0.70 logMAR. Ocular imaging showed no iris defect or foveal hypoplasia. Eye movement recordings showed a typical infantile nystagmus waveform. Visual fields were normal. The pattern and flash visual evoked potentials were normal and show no evidence of crossed asymmetry. Father had BCVA of OD 0.00 and OS 0.00 logMAR, he showed no ocular phenotype, confirmed on imaging and functional testing. To classify the p.(Gly72Arg) variant, multiple in silico algorithms were used to predict the impact of this highly conserved amino acid substitution which was found to be consistently damaging.
Conclusions :
There have been few reports of PAX6 non-penetrance, with one other case reported of an unaffected mother carrying a missense mutation upstream of the homeodomain, p.(Arg208Gln), who had a child with fully penetrant aniridia. Accurate genetic testing with segregation analysis is important for families, to enable informed genetic counselling and access to/development of potential therapies.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.