Abstract
BackgroundCongenital cataract is a Mendelian disorder that frequently causes blindness in infants. To date, various cataract-associated loci have been mapped; more than 30 genes have been identified by linkage analysis. However, the pathogenic loci in some affected families are still unknown, and new research strategies are needed. In this study, we used linkage-exome combinational analysis to further investigate the pedigree of a four-generation Chinese family with autosomal dominant coralliform cataract.MethodsWe combined whole exome sequencing and linkage analysis to identify the causative mutation. The exome capture and next-generation sequencing were used to sequence the protein-coding regions in the genome of the proband to identify rare mutations, which were further screened for candidate mutations in linkage regions. Candidate mutations were independently verified for co-segregation in the whole pedigree using Sanger sequencing.ResultsWe identified a C to A transversion at nucleotide position c.70 in exon 2 of CRYGD, a cataract-associated gene. This mutation resulted in a threonine substitution for proline at amino acid residue 24.ConclusionsWe identified a missense P24T mutation in CRYGD that was responsible for coralliform cataract in our studied family. Our findings suggest that the combination of exome sequencing and linkage analysis is a powerful tool for identifying Mendelian disease mutations that might be missed by the classic linkage analysis strategy.
Highlights
Congenital cataract is a Mendelian disorder that frequently causes blindness in infants
Whole exome sequencing is especially promising for research on monogenic disorders [9,10] since most of these disorders are caused by exonic mutations or splice-site mutations
Evaluation of exome sequencing data A strategy of whole exome sequencing by hybrid capture and Next-generation sequencing (NGS) was employed
Summary
Congenital cataract is a Mendelian disorder that frequently causes blindness in infants. Various cataract-associated loci have been mapped; more than 30 genes have been identified by linkage analysis. The pathogenic loci in some affected families are still unknown, and new research strategies are needed. We used linkage-exome combinational analysis to further investigate the pedigree of a four-generation Chinese family with autosomal dominant coralliform cataract. Linkage analysis is a classic strategy for mapping disease-associated loci in Mendelian inheritance pedigrees. This method requires large families, commonly a multi-generation pedigree with at least 6 to 12 affected individuals, to obtain high reliability and statistical significance. Next-generation sequencing (NGS) technology provides new avenues for uncovering genetic causes of human diseases. Whole exome sequencing is especially promising for research on monogenic disorders [9,10] since most of these disorders are caused by exonic mutations or splice-site mutations
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