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

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.

Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey

“…This mutation (c.70C>A) has been previously reported in the literature with unspecified phenotype [Ma et al, 2016], with lamellar cataract [Santhiya et al, 2002], and with coralliform cataract [Mackay et al, 2014]. Yang et al [2016], and Jia et al [2013] also identified the same mutation in families with coralliform cataract. Besides this, Zhuang et al [2015] demonstrated Mol Syndromol 2020;11:302-308 DOI: 10.1159/000510481 c.451_452insGACT (p.Tyr151) in CRYGD in a family with congenital nuclear cataract and showed that the mutant protein was highly insoluble and abnormally located.…”

Targeted Exome Sequencing of Congenital Cataracts Related Genes: Broadening the Mutation Spectrum and Genotype–Phenotype Correlations in 27 Chinese Han Families

“…coralliform, cerulean, lamellar) of CRYGD p.P24T. Our proband showed a coralliform cataract, which is one of the most common phenotype of this mutation 20 – 23 . CRYBB2 p.Q155X is another hotspot for mutation in congenital cataracts 13 , 24 , 25 .…”

A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family

“…Most of these genes include crystalline genes ( CRYAA , CRYAB, CRYBB1 , CRYBB2 , CRYBB3 , CYRBA1 , CRYBA3 , CRYBA4 , CRYGA , CRYGB , CRYGC , CRYGD , and CRYGS ) [6], membrane transport genes ( MIP ) [7], and gap junction proteins ( GJA3 and GJA8 ) [8]. The remaining known mutations are found in genes encoding growth and transcription factors, such as HSF4 , MAF , PITX3 , and PAX6 [9]. However, it was discovered that COL4A1 gene mutations were associated with ADCC in French families [10],[11], and there were rare reports that the type IV collagen , αlpha1 ( COL4A1 ) gene was associated with non-syndromic, autosomal dominant congenital cataract.…”