Analysis of Phenotypes Associated with Deficiency of PAX6 Haplotypes in Chinese Aniridia Families

Abstract

Objective

To examine the clinical phenotype and genetic deficiencies present in Chinese aniridia families with PAX6 haplotype deficiency.

Methods

A comprehensive questionnaire and ophthalmological assessments were administered to both affected patients and unaffected relatives. The clinical feature analysis included the evaluation of visual acuity, intraocular pressure, slit-lamp anterior segment examination, fundus photography, and spectral domain optical coherence tomography. To identify the mutation responsible for aniridia, targeted next-generation sequencing was used as a beneficial technique.

Results

A total of 4 mutations were identified, consisting of two novel frameshift mutations (c.314delA, p.K105Sfs*33 and c.838_845dup AACACACC, p.S283Tfs*85), along with two recurring nonsense mutations (c.307C>T, p.R103X and c.619A>T, p.K207*). Complete iris absence, macular foveal hypoplasia, and nystagmus were consistent in these PAX6 haplotype-deficient Chinese aniridia families, while corneal lesions, cataracts, and glaucoma exhibited heterogeneity both among the families and within the same family.

Conclusion

In our study, two novel PAX6 mutations associated with aniridia were identified in Chinese families, which expanded the phenotypic and genotypic spectrum of PAX6 mutations. We also analyzed the clinical characteristics of PAX6 haplotype deficiency in Chinese aniridia families.

References

[1] Guo R, Zhang X, Liu A, et al.. Novel clinical presentation and PAX6 mutation in families with congenital aniridia. Front Med (Lausanne), 2022, 9: 1042588

[2] Ochi S, Manabe S, Kikkawa T, et al.. Thirty Years’ History since the Discovery of PAX6: From Central Nervous System Development to Neurodevelopmental Disorders. Int J Mol Sci, 2022, 23(11): 6115

[3] Nguyen HH, Pham CM, Nguyen HTT, et al.. Novel mutations of the PAX6, FOXC1, and PITX2 genes cause abnormal development of the iris in Vietnamese individuals. Mol Vis, 2021, 27: 555-563

[4] Ansari M, Rainger J, Hanson IM, et al.. Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome. PLoS One, 2016, 11(4): e0153757

[5] Lima Cunha D, Arno G, Corton M, et al.. The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye. Genes (Basel), 2019, 10(12): 1050

[6] Tzoulaki I, White IM, Hanson IM, et al.. PAX6 mutations: genotype-phenotype correlations. BMC Genet, 2005, 6: 27

[7] Hingorani M, Hanson I, van Heyningen V, et al.. Aniridia. Eur J Hum Genet, 2012, 20(10): 1011-1017

[8] Glaser T, Walton DS, Maas RL, et al.. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet, 1992, 2(3): 232-239

[9] Kit V, Cunha DL, Hagag AM, et al.. Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia. JCI Insight, 2021, 6(14): e148406

[10] Thomas MG, Kumar A, Mohammad S, et al.. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity?. Ophthalmology, 2011, 118(8): 1653-1660

[11] Lagali N, Wowra B, Fries FN, et al.. PAX6 Mutational Status Determines Aniridia-Associated Keratopathy Phenotype. Ophthalmology, 2020, 127(2): 273-275

[12] Jin X, Chen L, Wang D, et al.. Novel compound heterozygous mutation in the POC1B gene underlie peripheral cone dystrophy in a Chinese family. Ophthalmic Genet, 2018, 39(3): 300-306

[13] Jin X, Qu LH, Hou BK, et al.. Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family. Biosci Rep, 2016, 36(1): e00289

[14] Jin X, Liu W, Qv LH, et al.. A novel variant in PAX6 as the cause of aniridia in a Chinese family. BMC Ophthalmol, 2021, 21(1): 225

[15] Krause MA, Trout KL, Lauderdale JD, et al.. Visual Acuity in Aniridia and WAGR Syndrome. Clin Ophthalmol, 2023, 17: 1255-1261

[16] Lima Cunha D, Owen N, Tailor V, et al.. PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism. Eur J Hum Genet, 2021, 29(2): 349-355

[17] Tarilonte M, Morin M, Ramos P, et al.. Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia. Front Genet, 2018, 9: 479

[18] Pedersen HR, Baraas RC, Landsend ECS, et al.. PAX6 Genotypic and Retinal Phenotypic Characterization in Congenital Aniridia. Invest Ophthalmol Vis Sci, 2020, 61(5): 14

[19] You B, Zhang X, Xu K, et al.. Mutation spectrum of PAX6 and clinical findings in 95 Chinese patients with aniridia. Mol Vis, 2020, 26: 226-234

[20] Daruich A, Robert MP, Leroy C, et al.. Foveal Hypoplasia Grading in 95 Cases of Congenital Aniridia: Correlation to Phenotype and PAX6 Genotype. Am J Ophthalmol, 2022, 237: 122-129

[21] Wang JD, Zhang JS, Xiong Y, et al.. Congenital aniridia with cataract: case series. BMC Ophthalmol, 2017, 17(1): 115

[22] Samant M, Chauhan BK, Lathrop KL, et al.. Congenital aniridia: etiology, manifestations and management. Expert Rev Ophthalmol, 2016, 11(2): 135-144

[23] van Velthoven AJH, Utheim TP, Notara M, et al.. Future directions in managing aniridia-associated keratopathy. Surv Ophthalmol, 2023, 68(5): 940-956

[24] Latta L, Ludwig N, Krammes L, et al.. Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia. Ocul Surf, 2021, 19: 115-127

[25] Bajwa A, Burstein E, Grainger RM, et al.. Anterior chamber angle in aniridia with and without glaucoma. Clin Ophthalmol, 2019, 13: 1469-1473

[26] Glaser T, Jepeal L, Edwards JG, et al.. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet, 1994, 7(4): 463-471

[27] Lagali N, Wowra B, Fries FN, et al.. Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations. Ocul Surf, 2020, 18(1): 130-140

[28] Vasilyeva TA, Marakhonov AV, Voskresenskaya AA, et al.. Analysis of genotype-phenotype correlations in PAX6-associated aniridia. J Med Genet, 2021, 58(4): 270-274

[29] Landsend ECS, Lagali N, Utheim TP, et al.. Congenital aniridia — A comprehensive review of clinical features and therapeutic approaches. Surv Ophthalmol, 2021, 66(6): 1031-1050

[30] Reis LM, Sorokina EA, Dudakova L, et al.. Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders. Hum Mol Genet, 2021, 30(17): 1591-1606