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

• DOI: 10.1038/ejhg.2013.268
• Publication Date: 2013-11-27T11:34:15Z
• Authors: Ivan Prokudin; Cas Simons; John R Grigg; Rebecca Storen; Vikrant Kumar; Zai Y Phua; James Smith; Maree Flaherty; Sonia Davila; Robyn V Jamieson
• Keywords: Exome sequencing; Male; 0301 basic medicine; 2716 Genetics (clinical); PAX6 Transcription Factor; DNA Mutational Analysis; 610; Penetrance; Connexins; 03 medical and health sciences; 1311 Genetics; Microphthalmia; Growth Differentiation Factor 3; Peters anomaly; Humans; Paired Box Transcription Factors; Exome; gamma-Crystallins; Eye Proteins; Homeodomain Proteins; Cataract/microcornea; Eye Diseases, Hereditary; Pedigree; 3. Good health; Coloboma; Repressor Proteins; 2700 Medicine; Cytochrome P-450 CYP1B1; Mutation; ATP-Binding Cassette Transporters; Female

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.