Ultraspecific Multiplexed Detection of Low-Abundance Single-Nucleotide Variants by Combining a Masking Tactic with Fluorescent Nanoparticle Counting

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

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Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Genetics in Medicine ◽

10.1038/s41436-020-01078-6 ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Hélène Morel ◽

Olivier Milleron ◽

Laurent Gouya ◽

Christine Francannet ◽

...

Keyword(s):

Marfan Syndrome ◽

Somatic Mosaicism ◽

Variant Calling ◽

Copy Number Variations ◽

Pathogenic Variant ◽

Single Nucleotide Variants ◽

Bioinformatics Analyses ◽

Single Nucleotide ◽

Fbn1 Gene ◽

Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00412-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fatao Liu ◽

Yongsheng Li ◽

Dongjian Ying ◽

Shimei Qiu ◽

Yong He ◽

...

Keyword(s):

Gene Mutations ◽

Large Cell ◽

Molecular Signatures ◽

Single Nucleotide Variants ◽

Oncogenic Signaling ◽

Single Nucleotide ◽

Whole Exome ◽

Deadly Disease ◽

Oncogenic Signaling Pathways ◽

Neuroendocrine Carcinomas

AbstractNeuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

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Missense RHD single nucleotide variants induce weakened D antigen expression by altering splicing and/or protein expression

Transfusion ◽

10.1111/trf.16538 ◽

2021 ◽

Author(s):

Loann Raud ◽

Marlène Le Tertre ◽

Léonie Vigneron ◽

Chandran Ka ◽

Gaëlle Richard ◽

...

Keyword(s):

Protein Expression ◽

Antigen Expression ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

D Antigen

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scSNV: accurate dscRNA-seq SNV co-expression analysis using duplicate tag collapsing

Genome Biology ◽

10.1186/s13059-021-02364-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Gavin W. Wilson ◽

Mathieu Derouet ◽

Gail E. Darling ◽

Jonathan C. Yeung

Keyword(s):

Genetic Variants ◽

False Positive ◽

Variant Calling ◽

Call Rate ◽

Rna Seq ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Variant Call ◽

Two Samples ◽

Co Detection

AbstractIdentifying single nucleotide variants has become common practice for droplet-based single-cell RNA-seq experiments; however, presently, a pipeline does not exist to maximize variant calling accuracy. Furthermore, molecular duplicates generated in these experiments have not been utilized to optimally detect variant co-expression. Herein, we introduce scSNV designed from the ground up to “collapse” molecular duplicates and accurately identify variants and their co-expression. We demonstrate that scSNV is fast, with a reduced false-positive variant call rate, and enables the co-detection of genetic variants and A>G RNA edits across twenty-two samples.

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