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Eur J Hum Genet. 2014 Jul;22(7):907-15. doi: 10.1038/ejhg.2013.268. Epub 2013 Nov 27.

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.

Author information

1
1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia.
2
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
3
1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
4
1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia [3] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
5
Human Genetics, Genome Institute of Singapore, Singapore.
6
Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
7
1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia [3] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia [4] Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, Australia.

Abstract

Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/microphthalmia.

PMID:
24281366
PMCID:
PMC4060118
DOI:
10.1038/ejhg.2013.268
[Indexed for MEDLINE]
Free PMC Article

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