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Title: Screen and Characterize the Disease-Causing Mutations for Kuwaiti Family having Autosomal Dominant Congenital Cataracts
Authors: Taiba A. Al-Barjes 
Supervisor: Dr. Suad AlFadhli
Keywords: Screen : Dominant
Issue Date: 2017
Publisher:  Kuwait university - college of graduate studies
Abstract: Cataracts are an eye abnormality; often known as lens opacities. Congenital cataract is an early onset inherited form of cataracts that is diagnosed at birth, and considered the main reason of reversible blindness in children. Several members of a multigenerational Kuwaiti family diagnosed with autosomal dominant congenital cataract (adCC) were recruited from Al-Bahar Eye Centre. Clinical examinations and assessments revealed a complex cataract phenotype with microcornea. DNA was extracted from peripheral blood of four affected and four unaffected members. Three methods were used to investigate mutations: i. whole genome linkage analysis using Affymetrix Gene Chip Human Mapping 250K Arrays, ii. direct Sanger sequencing to screen candidate genes for mutations and single nucleotide polymorphisms (SNPs), and iii. Whole-Exome Sequencing (WES) using NextSeq Illumina platform. Linkage analysis revealed three high LOD scores (2.4, 2 and 1.75) for two distinguished loci 22q13.31 and 3q22. LEPREL1 and WNT7b genes were picked for Sanger sequencing, but both showed no significant mutations and SNPs in their coding region, therefore WES was used as an alternative method and resulted in the discovery of many novel mutations in various genes (CRYAA, CELSR1, PKDREJ, P2RX5, UHRF1, SRD5A2, ZP4, LYST, SYNE2 and SLC25A5), which were predicted to play a role in cataractogenesis and/or microcornea. The most prominent mutations were a novel 2-nt frameshift deletion in exon 3 of CRYAA gene, and a 1-nt deletion in the exon/intron boundaries of CELSR1 gene located 18-bp from exon 7. These two mutations are highly implicated with cataract and/or microcornea. So far, our lab is the only lab in Kuwait investigating the molecular genetics of cataract, and this current family is the third one with novel mutations. WES proved to be a very successful tool for the discovery of disease-causing mutations. Herein, we report finding many novel mutations that we suspect act together to play an important role in the manifestation of complex cataract phenotype associated with microcornea. We also discovered novel deletions in the CRYAA and CELSR1 genes that may have contributed to the development of congenital cataract. However, more research in this field is required to reach a better understanding of the disease‟s development.
Appears in Programs:2050 Molecular Biology

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