Search

Purpose. To identify likely pathogenic variants in three families with congenital cataracts via panel-based exome sequencing. Methods. A panel containing 153 genes associated with congenital cataracts was designed. Genes were selected through reference to databases including the Human Gene Mutation Database (HGMD), Online Mendelian Inheritance in Man (OMIM), Genetic Home Reference, and the latest peer-reviewed publications on the genetics of hereditary cataracts. Panel-based exome sequencing was performed with the Illumina HiSeq X-Ten platform, and then the identified variants were confirmed with Sanger sequencing and evaluated according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results. Three likely pathogenic variants were found. A novel CRYBB2: c.230G > T p.G77V variant was identified in family A, a novel CRYBB2: c.230G > A p.G77D variant was identified in family B, and a novel CRYGD: c.475delG p.A159Pfs∗9 variant was identified in family C. Conclusion. Panel-based exome sequencing revealed three likely pathogenic variants in three unrelated Chinese families with congenital cataracts. These data expand the genetic spectrum associated with congenital cataracts. [ABSTRACT FROM AUTHOR]

Purpose: To identify the genetic defect in a three-generation Chinese family with congenital cataracts. Methods: The phenotype of a three-generation Chinese family with congenital cataract was recruited. Detailed family history and clinical data of the family were recorded. Candidate genes sequencing was performed to screen out the disease-causing mutation. Bioinformatics analysis was performed to predict the function of mutant gene. Results: The phenotype of the family was identified as nuclear cataract. Direct sequencing revealed a c.161 G > T transversion in exon 1 of crystallin alpha-A (CRYAA). This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that the 54th amino acid position was highly conserved and the mutation R54L caused an increase of local hydrophobicity around the substitution site. Conclusions: This study identified a novel disease-causing mutation c.161 G>T (p.R54L) in CRYAA in a Chinese family with autosomal dominant nuclear cataracts, this is the first report relating a G > T mutation in CRYAA leading to congenital nuclear cataract. [ABSTRACT FROM AUTHOR]

A notable behavioural feature of X-linked retinoschisis (XLRS) is extensive structural schisis (splitting) of the outer plexiform and inner nuclear layers of the neurosensory retina, which is partly combined with complications related to vitreous hemorrhage, macular holes and retinal detachment. The present study aimed to identify the pathogenic gene mutation in a three-generation Chinese family with XLRS by whole-exome sequencing (WES). The clinical information of a three-generation Chinese family with cases of XLRS was collected. WES was performed for the proband. A comparison with the human reference genome sequence (hg38) and bioinformatic analysis were performed to reveal putative variants and Sanger sequencing was applied to verify mutations in this family and healthy control participants. Intraretinal cystic spaces were detected by optical coherence tomography imaging. Structures of the wild-type and mutant retinoschisin 1 (RS1) protein were modelled by PyMol. Almost all patients had a history of vision loss and abnormal blue-purple colour vision; however, the phenotypes of the 4 patients were distinctly different. There was no linear correlation between phenotypic severity and age. A recurrent RS1 (Xp22.2) mutation (NM_000330: c.559C>T) was detected, resulting in the p.Q187X variant. According to the protein model, this variant is likely pathogenic. The present study was the first to report that RS1:c.559C>T induces XLRS in a three-generation Chinese pedigree, with the mutation leading to premature termination of translation of the RS1 protein. WES was able to diagnose XLRS, which has the characteristics of clinical and genetic heterogeneity. [ABSTRACT FROM AUTHOR]

Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that causes visual impairment and childhood blindness. The purpose of this study was to identify the genetic defect associated with autosomal dominant congenital perinuclear cataract in a Chinese family. A detailed family history and clinical data of the family were recorded, and candidate gene sequencing was performed to screen for mutation-causing disease in our study. Direct sequencing revealed a c.601G>A (p.E201K) transversion in exon 2 of GJA8. This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members or 100 unrelated controls. The function and mechanism of novel GJA8 point mutation E201K in Chinese patients were then investigated in this study. We found E201K aberrantly located in cytoplasm and prevented its location in the plasma membrane. Induction of E201K expression led to a decrease in cell growth and viability by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Our study provides important evidence that GJA8 is a disease-causing gene for congenital cataract and that mutation of GJA8 has a potential causative effect. [ABSTRACT FROM AUTHOR]

Purpose: To identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataract. Methods: Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci associated with cataracts. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. Results: Linkage analysis was obtained at markers D1S1653 (LOD score [ Z] = 1.50, recombination fraction [θ] = 0.0) and D1S498 (LOD score Z = 0.90, recombination fraction [θ] = 0.0), which encompasses the connexin 50 gene ( GJA8). Sequencing the coding regions of GJA8 revealed a novel, heterozygous c.773C>T transition that resulted in the substitution of a highly conserved serine by phenylalanine at codon 258 (S258F). Bioinformatics analysis showed that the mutation altered the hydrophobicity and secondary structure of the protein. This mutation co-segregated with the disease phenotype in all affected individuals and was not found in the unaffected family members or in 100 normal unrelated individuals. Conclusions: This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract. [ABSTRACT FROM AUTHOR]