Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma

Abstract

Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.

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Fig. 1: Schematic representation of all likely pathogenic variants identified in FZD5 with protein domains.

References

  1. 1.

    Patel A, Sowden JC. Genes and pathways in optic fissure closure. Semin Cell Dev Biol. 2019;91:55–65.

    CAS  Article  Google Scholar 

  2. 2.

    Graw J. Eye development. Curr Top Dev Biol. 2010;90:343–86.

    Article  Google Scholar 

  3. 3.

    Onwochei BC, Simon JW, Bateman JB, Couture KC, Mir E. Ocular colobomata. Sur Ophthalmol. 2000;45:175–94.

    CAS  Article  Google Scholar 

  4. 4.

    Gestri G, Bazin-Lopez N, Scholes C, Wilson SW. Cell behaviors during closure of the choroid fissure in the developing eye. Front Cell Neurosci. 2018;12:42.

    Article  Google Scholar 

  5. 5.

    Zagozewski JL, Zhang Q, Eisenstat DD. Genetic regulation of vertebrate eye development. Clin Genet. 2014;86:453–60.

    CAS  Article  Google Scholar 

  6. 6.

    Plaisancie J, Ceroni F, Holt R, Zazo Seco C, Calvas P, Chassaing N, et al. Genetics of anophthalmia and microphthalmia. Part 1: non-syndromic anophthalmia/microphthalmia. Hum Genet. 2019;138:799–830.

    CAS  Article  Google Scholar 

  7. 7.

    AS AL, Gregory-Evans CY, Gregory-Evans K. An update on the genetics of ocular coloboma. Hum Genet. 2019;138:865–80.

    Article  Google Scholar 

  8. 8.

    Shah SP, Taylor AE, Sowden JC, Ragge NK, Russell-Eggitt I, Rahi JS, et al. Anophthalmos, microphthalmos, and typical coloboma in the United Kingdom: a prospective study of incidence and risk. Invest Ophthalmol Vis Sci. 2011;52:558–64.

    Article  Google Scholar 

  9. 9.

    Chassaing N, Causse A, Vigouroux A, Delahaye A, Alessandri JL, Boespflug-Tanguy O, et al. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014;86:326–34.

    CAS  Article  Google Scholar 

  10. 10.

    Liu C, Widen SA, Williamson KA, Ratnapriya R, Gerth-Kahlert C, Rainger J, et al. A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma. Hum Mol Genet. 2016;25:1382–91.

    CAS  Article  Google Scholar 

  11. 11.

    Rainger J, Williamson KA, Soares DC, Truch J, Kurian D, Gillessen-Kaesbach G, et al. A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma. Hum Mutat. 2017;38:942–6.

    CAS  Article  Google Scholar 

  12. 12.

    Fujimura N. WNT/beta-catenin signaling in vertebrate eye development. Front Cell Dev Biol. 2016;4:138.

    Article  Google Scholar 

  13. 13.

    Liu C, Nathans J. An essential role for frizzled 5 in mammalian ocular development. Development. 2008;135:3567–76.

    CAS  Article  Google Scholar 

  14. 14.

    Liu C, Bakeri H, Li T, Swaroop A. Regulation of retinal progenitor expansion by Frizzled receptors: implications for microphthalmia and retinal coloboma. Hum Mol Genet. 2012;21:1848–60.

    CAS  Article  Google Scholar 

  15. 15.

    Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O’Roak BJ, Gilissen C, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012;44:440–4.

  16. 16.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  17. 17.

    Srour M, Chitayat D, Caron V, Chassaing N, Bitoun P, Patry L, et al. Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. Am J Hum Genet. 2013;93:765–72.

    CAS  Article  Google Scholar 

  18. 18.

    Rainger J, Pehlivan D, Johansson S, Bengani H, Sanchez-Pulido L, Williamson KA, et al. Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations. Am J Hum Genet. 2014;94:915–23.

    CAS  Article  Google Scholar 

  19. 19.

    Kalaskar VK, Alur RP, Li LK, Thomas JW, Sergeev YV, Blain D, et al. High-throughput custom capture sequencing identifies novel mutations in coloboma-associated genes: mutation in DNA-binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma. Hum Mutat. 2019;41:678–95.

    Article  Google Scholar 

  20. 20.

    Patel N, Khan AO, Alsahli S, Abdel-Salam G, Nowilaty SR, Mansour AM, et al. Genetic investigation of 93 families with microphthalmia or posterior microphthalmos. Clin Genet. 2018;93:1210–22.

    CAS  Article  Google Scholar 

  21. 21.

    Robitaille JM, Zheng B, Wallace K, Beis MJ, Tatlidil C, Yang J, et al. The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease. Brit J Ophthalmol. 2011;95:574–9.

    Article  Google Scholar 

  22. 22.

    Bang I, Kim HR, Beaven AH, Kim J, Ko SB, Lee GR, et al. Biophysical and functional characterization of Norrin signaling through Frizzled4. Proc Natl Acad Sci USA. 2018;115:8787–92.

    CAS  Article  Google Scholar 

  23. 23.

    Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116:883–95.

    CAS  Article  Google Scholar 

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Acknowledgements

We acknowledge generous support from the patients and their families as well as Claire Jeanton-Scaramouche for her precious help.

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Correspondence to Julie Plaisancié.

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Aubert-Mucca, M., Pernin-Grandjean, J., Marchasson, S. et al. Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0695-8

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