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Owen M. Siggs, Shari Javadiyan, Shiwani Sharma, Kathryn P Burdon, Jamie E Craig; Partial duplication of CRYBB1 as a novel genetic mechanism for autosomal dominant congenital cataract. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2518.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital cataract is a heterogeneous inherited disease, often caused by mutation of one of several crystallin genes. After sequencing a panel of candidate genes in a large congenital cataract pedigree, and finding no suspected pathogenic variants, we sought to identify the underlying genetic cause by exome sequencing.
Whole exome sequencing was performed on 11 members (6 affected, 5 unaffected) of a five-generation autosomal dominant pedigree. This dataset was then subjected to genome-wide linkage analysis using LINKDATAGEN and MERLIN, variant calling and annotation with SAMtools and ANNOVAR, and copy number variant analysis with SAMtools and CoNIFER.
The congenital cataract phenotype showed strong linkage (LODmax of 3.3) to a region of chromosome 22 encompassing the crystallin genes CRYBB1 and CRYBA4. Despite this, no rare variants were apparent in either gene, nor in any of the other 15 protein-coding genes within the interval. However, copy number analysis revealed a 30 kilobase duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, and is predicted to create a gain of function or dominant negative allele through the absence of exon 6.
These results reveal a new genetic mechanism for the development of congenital cataract, which was not detected by conventional candidate gene sequencing nor by exome variant calling. This highlights the importance of investigating copy number variation in inherited eye disease, and in particular, the significance of partial gene duplications.
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