Phenotypic Variation in a Four-Generation Family with Aniridia Carrying a NovelPAX6Mutation

Abstract

Aniridia is a congenital disease that affects almost all eye structures and is primarily caused by loss-of-function mutations in the PAX6 gene. The degree of vision loss in aniridia varies and is dependent on the extent of foveal, iris, and optic nerve hypoplasia and the presence of glaucoma, cataracts, and corneal opacification. Here, we describe a 4-generation family in which 7 individuals across 2 generations carry a novel disease-causing frameshift mutation (NM_000280.4(PAX6):c.565TC>T) in PAX6. This mutation results in an early stop codon in exon 8, which is predicted to cause nonsense-mediated decay of the truncated mRNA and a functionally null PAX6 allele. Family members with aniridia showed differences in multiple eye phenotypes including iris and optic nerve hypoplasia, congenital and acquired corneal opacification, glaucoma, and strabismus. Visual acuity ranged from 20/100 to less than 20/800. Patients who required surgical intervention for glaucoma or corneal opacification had worse visual outcomes. Our results show that family members carrying a novel PAX6 frameshift mutation have variable expressivity, leading to different ocular comorbidities and visual outcomes.

The Ocular Neural Crest: Specification, Migration, and Then What?

“…Notably, mutations in Pax6 are more typically associated with aniridia, a panocular congenital disease characterized by foveal hypoplasia, optic nerve hypoplasia, limbal stem cell deficiency, and varying degrees of iris hypoplasia (reviewed in Lim et al, 2017 ; Sannan et al, 2017 ; Syrimis et al, 2018 ; Wawrocka and Krawczynski, 2018 ; Lima Cunha et al, 2019 ; Lee et al, 2020 ; Tripathy and Salini, 2020 ). However, phenotypic variation of the same Pax6 gene mutation has shown both aniridia and PA within one family ( Wang et al, 2018 ), and PA has been associated with aniridia in more than 10% of cases ( Dolezal et al, 2019 ).…”

Clinical outcomes and visual prognostic factors in congenital aniridia

“…Twelve patients were members of a previously described 4-generation family, in which genetic testing on generations iii, and iv showed a splice-site mutation (c.565TC > T) in PAX6 (NM_000280.4) [ 27 ]. Seven additional patients were related to this family by marriage (Fig.…”

Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders

“…The majority of the submitted variants involve nonsense or frameshift pathogenic variants resulting in premature termination codons and haploinsufficiency [ 85 , 86 ] and these represent 75–80% of aniridia cases. Numerous studies have described PAX6 pathogenic variants as resulting in a complete penetrance of aniridic ocular changes; however, single pathogenic variants result in a wide variety and severity of phenotypes [ 90 , 91 ]. Some reports have suggested that the level of disease severity is possibly correlated with the level of PAX6 expression with loss of function pathogenic variants resulting in the most severe cases [ 86 ].…”

“…Some reports have suggested that the level of disease severity is possibly correlated with the level of PAX6 expression with loss of function pathogenic variants resulting in the most severe cases [ 86 ]. Still, this does not explain the varying severity and onset of pathology amongst family members with identical pathogenic variants [ 90 ]. Compound heterozygous pathogenic variants in PAX6 are thought to be lethal; however, studies have described such patients with mortality in late gestation or shortly after birth with severe craniofacial and ocular malformations [ 85 ].…”