scholarly journals Whole Exome Sequencing Identifies a Novel COL1A1 Missense Mutation Causing Dentinogenesis Imperfecta Type I Without Skeletal Abnormalities

2021 ◽  
Author(s):  
Yuting Zeng ◽  
Yuhua Pan ◽  
Jiayao Mo ◽  
Zhiting Ling ◽  
Lifang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Blue Staining ◽  
Nanoindentation Test ◽  
Type I ◽  
Dentinogenesis Imperfecta ◽  
Whole Exome ◽  
Blue Sclerae ◽  
The Impact

Abstract Background：Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, blue sclerae and dentinogenesis imperfecta (DGI), which are mainly caused by a mutation of the COL1A1 or COL1A2 genes that encode type I procollagen.Methods: The ultrastructure of dentin was analyzed by micro-CT, scanning electron microscopy, energy-dispersive spectroscopy analysis, nanoindentation test and Toluidine Blue Staining. Whole-exome sequencing (WES) was performed to identify the pathogenic gene. The function of the mutant COL1A1 was studied by real-time PCR, western blotting, subcellular localization. Functional analysis in dental pulp stem cells (DPSCs) was also performed to explore the impact of the identified mutation on this phenotype. Results: WES identified a missense mutation (c.1463G > C) in exon 22 of the COL1A1 gene. However, the cases reported herein only exhibited DGI-I in the clinical phenotype, there is no bone disease and any other common abnormal symptom caused by COL1A1 mutation. In addition, ultrastructural analysis of the tooth affected with non-syndromic DGI-I showed that the abnormal dentin was accompanied by disruption of odontoblast polarization, reduced numbers of odontoblasts, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. What’s more, the odontoblast differentiation ability based on DPSCs that were isolated and cultured from the DGI-I patient was enhanced compared with those from an age-matched, healthy control.Conclusion: This study helped the family members to understand the disease progression and provided new insights into the phenotype-genotype association in collagen-associated diseases and improve clinical diagnosis of OI/DGI-I.

scholarly journals Clinical and Molecular Update on the Fourth Reported Family with Hamamy Syndrome

2021 ◽  
pp. 1-9
Author(s):  
André Mégarbané ◽  
Sayeeda Hana ◽  
Hala Mégarbané ◽  
Christel Castro ◽  
Sylvain Baulande ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Bone Fragility ◽  
Dentinogenesis Imperfecta ◽  
Review Of The Literature ◽  
Obligate Carrier ◽  
Whole Exome ◽  
Sequencing Studies

We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe telecanthus, abnormal ears, dentinogenesis imperfecta, and bone fragility. Whole-exome sequencing studies performed on the 2 affected individuals and one obligate carrier revealed the presence of a homozygous c.503G&#x3e;A (p.Arg168His) missense mutation in <i>IRX5</i> in both sibs, not reported in any other family. Review of the literature and differential diagnoses are discussed.

scholarly journals Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding ERCC6 Gene in a Taiwanese Boy with Cockayne Syndrome

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1230
Author(s):  
Ching-Ming Lin ◽  
Jay-How Yang ◽  
Hwei-Jen Lee ◽  
Yu-Pang Lin ◽  
Li-Ping Tsai ◽  
...  
Keyword(s):  
Protein Stability ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
3D Structure ◽  
Cockayne Syndrome ◽  
Structure Stability ◽  
Homozygous Missense Mutation ◽  
Whole Exome ◽  
The Impact

Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (ERCC6) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Methods: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. Results: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER’s model but destabilized the Alphafold’s modeled structure. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability.

scholarly journals Whole exome sequencing identified a novel missense mutation in EPM2A underlying Lafora disease in a Pakistani family

Seizure ◽  
2017 ◽  
Vol 51 ◽  
pp. 200-203
Author(s):  
Zain Aslam ◽  
Eungi Lee ◽  
Mazhar Badshah ◽  
Muhammad Naeem ◽  
Changsoo Kang
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Pakistani Family ◽  
Lafora Disease ◽  
Whole Exome

scholarly journals Multiple Variant Calling Pipelines in Wheat Whole Exome Sequencing

2021 ◽  
Vol 22 (19) ◽  
pp. 10400
Author(s):  
H. Busra Cagirici ◽  
Bala Ani Akpinar ◽  
Taner Z. Sen ◽  
Hikmet Budak
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Variant Calling ◽  
High Sensitivity ◽  
Whole Exome ◽  
The Impact ◽  
Multiple Reference ◽  
Reference Genomes ◽  
Selection Of ◽  
Variant Identification

The highly challenging hexaploid wheat (Triticum aestivum) genome is becoming ever more accessible due to the continued development of multiple reference genomes, a factor which aids in the plight to better understand variation in important traits. Although the process of variant calling is relatively straightforward, selection of the best combination of the computational tools for read alignment and variant calling stages of the analysis and efficient filtering of the false variant calls are not always easy tasks. Previous studies have analyzed the impact of methods on the quality metrics in diploid organisms. Given that variant identification in wheat largely relies on accurate mining of exome data, there is a critical need to better understand how different methods affect the analysis of whole exome sequencing (WES) data in polyploid species. This study aims to address this by performing whole exome sequencing of 48 wheat cultivars and assessing the performance of various variant calling pipelines at their suggested settings. The results show that all the pipelines require filtering to eliminate false-positive calls. The high consensus among the reference SNPs called by the best-performing pipelines suggests that filtering provides accurate and reproducible results. This study also provides detailed comparisons for high sensitivity and precision at individual and population levels for the raw and filtered SNP calls.

Identification of a novel SBF2 missense mutation associated with a rare case of thrombocytopenia using whole-exome sequencing

2013 ◽  
Vol 36 (4) ◽  
pp. 501-506 ◽  
Author(s):  
Adel M. Abuzenadah ◽  
Galila F. Zaher ◽  
Ashraf Dallol ◽  
Ghazi A. Damanhouri ◽  
Adeel G. Chaudhary ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Rare Case ◽  
Whole Exome

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

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