Abstract
Purpose
Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family.
Methods
Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree.
Results
A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH2-terminal region of the gap junction protein GJA3 and found to co-segregate with disease.
Conclusion
We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.
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Acknowledgements
The present work is supported by grants from the National Institute for Health Research Biomedical Research Center at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology (UK), Moorfields Eye Hospital Special Trustees (UK), Moorfields Eye Charity (UK), and the Foundation Fighting Blindness (USA). Michel Michaelides is supported by an FFB Career Development Award. We thank the members of the family for taking part in this study.
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Berry, V., Ionides, A.C.W., Pontikos, N. et al. Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract. Eye 32, 1661–1668 (2018). https://doi.org/10.1038/s41433-018-0154-8
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DOI: https://doi.org/10.1038/s41433-018-0154-8
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