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New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

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Abstract

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

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Acknowledgements

We would like to thank the patients and their families for their participation in our study. We are grateful to Suzanne Broadgate for assisting with the coordination of the project. We thank the Centrum Menselijke Erfelijkheid laboratory, Leuven, Belgium, for the diagnostic PAX2 testing. We also thank Dr Jean-Philippe Bault for the ultrasound examinations performed on family 2. This work was supported by grants from Baillie Gifford, Visually Impaired Children Taking Action (VICTA) (http://www.victa.org.uk/), Microphthalmia, Anophthalmia, Coloboma Support (MACS) (http://www.macs.org.uk), Oxford Brookes University Central Research Fund, Retina France, Fondation Maladies Rares, Spanish Institute of Health Carlos III (CP12/03256), Spanish Ministry of Economy and Competitiveness (SAF2013–46943-R), Mutua Madrileña Foundation and Cátedra de Patrocinio UAM-IIS-FJD of Genomic Medicine (University Autónoma of Madrid). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], see http://www.ddduk.org/access.html for full acknowledgement.

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Author notes

  1. Marta Corton and Nicola Ragge: joint senior authors.

Authors and Affiliations

  1. Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK

    Fabiola Ceroni, Dorine Arjanne Bax, Richard James Holt & Nicola K Ragge

  2. Genetics Service, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain

    Domingo Aguilera-Garcia, Fiona Blanco-Kelly, Patricia Ramos, Maria Tarilonte, Cristina Villaverde, Luciana Rodrigues Jacy da Silva, Carmen Ayuso & Marta Corton

  3. Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain

    Domingo Aguilera-Garcia, Fiona Blanco-Kelly, Patricia Ramos, Maria Tarilonte, Cristina Villaverde, Luciana Rodrigues Jacy da Silva, Carmen Ayuso & Marta Corton

  4. Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, Toulouse, France

    Nicolas Chassaing & Patrick Calvas

  5. UMR 1056 Inserm, Université de Toulouse, Toulouse, France

    Nicolas Chassaing & Patrick Calvas

  6. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Fiona Blanco-Kelly & Helen Stewart

  7. Institute of Ophthalmology, University College London, London, UK

    Fiona Blanco-Kelly

  8. Medical Genetics Department, University Hospital Virgen de la Arrixaca, Murcia, Spain

    Maria Juliana Ballesta-Martínez & Maria Jose Sanchez-Soler

  9. West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK

    Lisa Cooper-Charles, Jonathan Bruty, Yvonne Wallis, Dominic McMullan & Michael Griffiths

  10. West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TG, UK

    Jonathan Hoffman & Nicola K Ragge

  11. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK

    David Bunyan

  12. Sheffield Clinical Genetics Department, Northern General Hospital, Sheffield, UK

    Alison Stewart

  13. Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Katherine Lachlan

  14. Human Genetics and Genomic Medicine, Southampton General Hospital, University of Southampton, Southampton, UK

    Katherine Lachlan

  15. Cheshire and Merseyside Genetics Service, Liverpool Women’s NHS Foundation Trust, Liverpool, UK

    Alan Fryer & Victoria McKay

  16. Department of Clinical Genetics, Centre de Référence “AnDDI Rares”, Poissy Hospital GHU PIFO, Poissy, France

    Joëlle Roume

  17. Fondation Ophtalmologique Adolphe-de-Rothschild, Paris, France

    Pascal Dureau

  18. Clinical Genetics Unit, St Georges University of London, London, UK

    Anand Saggar

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  1. Fabiola Ceroni
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  2. Domingo Aguilera-Garcia
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  3. Nicolas Chassaing
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  4. Dorine Arjanne Bax
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  5. Fiona Blanco-Kelly
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  6. Patricia Ramos
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  7. Maria Tarilonte
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  8. Cristina Villaverde
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  9. Luciana Rodrigues Jacy da Silva
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  10. Maria Juliana Ballesta-Martínez
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  11. Maria Jose Sanchez-Soler
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  12. Richard James Holt
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  13. Lisa Cooper-Charles
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  14. Jonathan Bruty
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  15. Yvonne Wallis
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  16. Dominic McMullan
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  17. Jonathan Hoffman
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  18. David Bunyan
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Correspondence to Nicola K Ragge.

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Ceroni, F., Aguilera-Garcia, D., Chassaing, N. et al. New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies. Hum Genet 138, 1027–1042 (2019). https://doi.org/10.1007/s00439-018-1875-2

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  • DOI: https://doi.org/10.1007/s00439-018-1875-2

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