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.

Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia

“…We did not find any other sequence variants in published gene lists for MAC (Deml et al, 2014; Prokudin et al, 2014) that were predicted to alter function and did not find any other cause for the eye defects in this child.…”

Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract

“…Several recent studies have employed exome sequencing of index patients or probands in multiple families in order to discover mutations in candidate genes underlying autosomal dominant and recessive forms of cataract [13,[17][18][19]. In this study, we have used trio-based exome sequencing to uncover a recurrent missense mutation in CRYGD (p.Pro24Thr) and two novel missense mutations in GJA8 (p.Leu7Pro, p.His98Pro) associated with autosomal dominant cataract in three nuclear families.…”

Whole exome sequencing reveals a novel de novo FOXC1 mutation in a patient with unrecognized Axenfeld–Rieger syndrome and glaucoma

“…A correct diagnosis is often only established after the identification of mutations in one of the known associated genes. Whole exome sequencing has been successfully employed to identify causative mutations in genetically and phenotypically heterogeneous developmental eye diseases allowing also the expansion of the phenotypes of known associated eye disease genes (Deml et al, 2014;Prokudin et al, 2014).…”