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


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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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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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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