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Min H.-Y.,Peking Union Medical College | Qiao P.-P.,University of Chinese Academy of Sciences | Qiao P.-P.,Binhai Genomics Institute | Qiao P.-P.,Tianjin Translational Genomics Center | And 21 more authors.
Chinese Medical Journal | Year: 2016

Background: Congenital cataract (CC) is the leading cause of visual impairment or blindness in children worldwide. Because of highly genetic and clinical heterogeneity, a molecular diagnosis of the lens disease remains a challenge. Methods: In this study, we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure, pedigree validation, and molecular dynamics (MD) simulation. Results: A novel 15 bp deletion on GJA8 (c.426_440delGCTGGAGGGGACCCT or p. 143_147delLEGTL) was detected in the family. The deletion, concerned with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 (Cx50), was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes. MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel, indicating the deletion as a dominant-negative mutation. Conclusions: The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs. © 2016 Chinese Medical Journal.


Dan S.,Capital Medical University | Yuan Y.,Binhai Genomics Institute | Yuan Y.,Tianjin Translational Genomics Center | Wang Y.,Binhai Genomics Institute | And 19 more authors.
PLoS ONE | Year: 2016

Background: Since the discovery of cell-free foetal DNA in the plasma of pregnant women, many non-invasive prenatal testing assays have been developed. In the area of skeletal dysplasia diagnosis, some PCR-based non-invasive prenatal testing assays have been developed to facilitate the ultrasound diagnosis of skeletal dysplasias that are caused by de novo mutations. However, skeletal dysplasias are a group of heterogeneous genetic diseases, the PCR-based method is hard to detect multiple gene or loci simultaneously, and the diagnosis rate is highly dependent on the accuracy of the ultrasound diagnosis. In this study, we investigated the feasibility of using targeted capture sequencing to detect foetal de novo pathogenic mutations responsible for skeletal dysplasia. Methodology/Principal Findings: Three families whose foetuses were affected by skeletal dysplasia and two control families whose foetuses were affected by other single gene diseases were included in this study. Sixteen genes related to some common lethal skeletal dysplasias were selected for analysis, and probes were designed to capture the coding regions of these genes. Targeted capture sequencing was performed on the maternal plasma DNA, the maternal genomic DNA, and the paternal genomic DNA. The de novo pathogenic variants in the plasma DNA data were identified using a bioinformatical process developed for low frequency mutation detection and a strict variant interpretation strategy. The causal variants could be specifically identified in the plasma, and the results were identical to those obtained by sequencing amniotic fluid samples. Furthermore, a mean of 97% foetal specific alleles, which are alleles that are not shared by maternal genomic DNA and amniotic fluid DNA, were identified successfully in plasma samples. Conclusions/Significance: Our study shows that capture sequencing of maternal plasma DNA can be used to non-invasive detection of de novo pathogenic variants. This method has the potential to be used to facilitate the prenatal diagnosis of skeletal dysplasia. © 2016 Dan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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