title: Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.
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.
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Prokudin
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: 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.
authors.forename: John R
authors.initials: JR
authors.lastname: Grigg
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Storen
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Zai Y
authors.initials: ZY
authors.lastname: Phua
authors.affiliation: Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Maree
authors.initials: M
authors.lastname: Flaherty
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.affiliation: 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.
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
mesh_terms: D018528:ATP-Binding Cassette Transporters; D017630:Connexins / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D055451:Growth Differentiation Factor 3; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D012097:Repressor Proteins / Q000235:genetics*; D038222:gamma-Crystallins / Q000235:genetics*; D000099264:Connexin 50
chemical_list: D018528:ATP-Binding Cassette Transporters; D017630:Connexins; D065633:Cytochrome P-450 CYP1B1; D005136:Eye Proteins; D055451:Growth Differentiation Factor 3; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D038222:gamma-Crystallins; D000099264:Connexin 50; C107991:ABCB6 protein, human; C522806:Crygc protein, human; C525974:GDF3 protein, human; C000605730:PAX6 protein, human; C585496:CYP1B1 protein, human