Purchase this article with an account.
Hiroyuki Kondo, Genji Nakamori, Eiichi Uchio, Tomoko Tahira, Ken Yamamoto, Akihiko Tawara; New Mutation in GJA8 gene is Associated with Unique Phenotype of Familial Microphthalmia with Anomalies of Iris and Lens. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1541.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
We report a Japanese family of 5 members with microphthalmia with anomalies of the iris and crystalline lens, and the causative gene was determined by exome sequencing.
Ophthalmic examinations were performed on five affected family members. DNA was extracted from 8 members including the 5 affected individuals, and used for genome-wide SNP genotyping and linkage analysis. A whole exon capture method was used in two affected siblings using SureSelect 50Mb kit followed by massively parallel sequencing using Illumina HiSeq2000 with a paired end of 100-bp reads. The sequence reads were aligned and filtered by synonymous variants and known SNPs. The functional significance of nonsynonymous variants were evaluated by SIFT and other programs. Segregation analysis for candidate variants was performed by Sanger sequencing for the 8 members.
The five patients had a uniform phenotype of microphthalmia, microcornea, anomalies of the iris including microcoria, and cataracts. The inheritance pattern suggested an autosomal dominant mutation. Whole genome exome sequencing of the two siblings determined that 21,076 and 21,026 were either exonic or splicing variants. Linkage analysis indicated that 9 regions scattered on 7 chromosomes were candidate gene regions. By filtering with further criteria (≥10x coverage, and ≥0.3 of a fraction), we identified 8 functionally significant variants. All were new variants, and six were nonsynonymous and two were deletion variants. Of the variants, we identified a c.G151A (p.D51N) change in the GJA8 gene. Codon 51 was highly conserved among the GJA8 homologues and orthologues. This variant cosegregated with the disease and was not found in 241 normal controls.
Mutations of GJA8 are known to cause congenital cataracts and the cataract-microcornea syndrome. The new microphthalmic phenotype is associated with a mutation in GJA8. We suggest that abnormal crystalline lens formation due to the mutant GJA8 may affect the normal development of the iris and other tissues in the anterior segment. However, the involvement of other novel variants is also being evaluated.
This PDF is available to Subscribers Only