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Hum Genet. 2019 Sep;138(8-9):1027-1042. doi: 10.1007/s00439-018-1875-2. Epub 2018 Feb 20.

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

Author information

1
Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
2
Genetics Service, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
3
Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
4
Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, Toulouse, France.
5
UMR 1056 Inserm, Université de Toulouse, Toulouse, France.
6
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
7
Institute of Ophthalmology, University College London, London, UK.
8
Medical Genetics Department, University Hospital Virgen de la Arrixaca, Murcia, Spain.
9
West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
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.
11
Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
12
Sheffield Clinical Genetics Department, Northern General Hospital, Sheffield, UK.
13
Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
14
Human Genetics and Genomic Medicine, Southampton General Hospital, University of Southampton, Southampton, UK.
15
Cheshire and Merseyside Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
16
Department of Clinical Genetics, Centre de Référence "AnDDI Rares", Poissy Hospital GHU PIFO, Poissy, France.
17
Fondation Ophtalmologique Adolphe-de-Rothschild, Paris, France.
18
Clinical Genetics Unit, St Georges University of London, London, UK.
19
Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK. nragge@brookes.ac.uk.
20
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. nragge@brookes.ac.uk.

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.

PMID:
29464339
DOI:
10.1007/s00439-018-1875-2
[Indexed for MEDLINE]

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