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Open Access Highly Accessed Research article

Combinational analysis of linkage and exome sequencing identifies the causative mutation in a Chinese family with congenital cataract

Xueyuan Jia1, Feng Zhang2, Jing Bai1, Linghan Gao1, Xuelong Zhang1, Haiming Sun1, Donglin Sun1, Rongwei Guan1, Wenjing Sun1, Lidan Xu1, Zhichao Yue1, Yang Yu1 and Songbin Fu13*

Author Affiliations

1 Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China

2 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China

3 Key Laboratory of Medical Genetics (Harbin Medical University), Heilongjiang Higher Education Institutions, Harbin, China

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BMC Medical Genetics 2013, 14:107  doi:10.1186/1471-2350-14-107

Published: 8 October 2013

Abstract

Background

Congenital 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.

Methods

We 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.

Results

We 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.

Conclusions

We 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.

Keywords:
Autosomal dominant congenital cataract; Whole exome sequencing; Linkage analysis; CRYGD; Coralliform cataract