scholarly journals Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

2019 ◽  
Author(s):  
Gonzalo Lopez ◽  
Karina L. Conkrite ◽  
Miriam Doepner ◽  
Komal S. Rathi ◽  
Apexa Modi ◽  
...  
Keyword(s):  
High Risk ◽  
Childhood Cancer ◽  
Structural Variation ◽  
Neuroblastoma Cell ◽  
Snp Array ◽  
Autism Spectrum ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Relative Paucity ◽  
Duplication Events

ABSTRACTNeuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma exhibits a relative paucity of somatic single nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design allowed for orthogonal validation and replication across platforms. SV frequency, type, and localization varied significantly among high-risk tumors. MYCN non-amplified high-risk tumors harbored an increased SV burden overall, including a substantial excess of tandem-duplication events across the genome. Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% of MYCN non-amplified high-risk tumors based on WGS and 10% in the SNP array cohort. Expression of SHANK2 was low across human-derived neuroblastoma cell lines and high-risk neuroblastoma tumors. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62×10-2 to 3.4×10-5) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08×10-13 to 2.38×10-30). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis in this childhood cancer.

scholarly journals Community-wide outbreak of hepatitis A in Latvia in 2008 – an update

2009 ◽  
Vol 14 (3) ◽  
Author(s):  
J Perevoščikovs ◽  
I Lucenko ◽  
S Magone ◽  
A Brila ◽  
J Curikova ◽  
...  
Keyword(s):  
High Risk ◽  
Molecular Analysis ◽  
Drug Users ◽  
Hepatitis A ◽  
Risk Groups ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Spread Of Infection

An outbreak of hepatitis A has been ongoing in Latvia with 2,817 confirmed cases reported between 20 November 2007 and 31 December 2008. Initially the spread of infection was due to transmission among drug users and other high-risk groups, as well as several outbreaks in Riga (affecting a school and a restaurant), but in the second half of the year led to a community-wide increase in the number of cases. Molecular analysis of 100 strains showed that 95 belonged to genotype IA, of which 89 were identical and six were single nucleotide variants of the same sequence.

scholarly journals Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yoshihiro Nawa ◽  
Hiroki Kimura ◽  
Daisuke Mori ◽  
Hidekazu Kato ◽  
Miho Toyama ◽  
...  
Keyword(s):  
Rare Variants ◽  
Adaptor Protein ◽  
Autism Spectrum ◽  
Case Group ◽  
Missense Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Next Generation Sequencing Technology ◽  
A Minor

AbstractDisabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

scholarly journals Rare single nucleotide variants in COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liubov O. Skorodumova ◽  
Alexandra V. Belodedova ◽  
Elena I. Sharova ◽  
Elena S. Zakharova ◽  
Liliia N. Iulmetova ◽  
...  
Keyword(s):  
Rare Variants ◽  
Snp Array ◽  
Promoter Sequence ◽  
Minor Allele ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Degenerative Disorder ◽  
Pcr Targeting

Abstract Background Keratoconus is a chronic degenerative disorder of the cornea characterized by thinning and cone-shaped protrusions. Although genetic factors play a key role in keratoconus development, the etiology is still under investigation. The occurrence of single-nucleotide polymorphisms (SNPs) associated with keratoconus in Russian patients is poorly studied. The purpose of this study was to validate whether three reported keratoconus-associated SNPs (rs1536482 near the COL5A1 gene, rs2721051 near the FOXO1 gene, rs1324183 near the MPDZ gene) are also actual for a Russian cohort of patients. Additionally, we investigated the COL5A1 promoter sequence for single-nucleotide variants (SNVs) in a subgroup of keratoconus patients with at least one rs1536482 minor allele (rs1536482+) to assess the role of these SNVs in keratoconus susceptibility associated with rs1536482. Methods This case-control study included 150 keratoconus patients and two control groups (main and additional, 205 and 474 participants, respectively). We performed PCR targeting regions flanking SNVs and the COL5A1 promoter, followed by Sanger sequencing of amplicons. The additional control group was genotyped using an SNP array. Results The minor allele frequency was significantly different between the keratoconus and control cohorts (main and combined) for rs1536482, rs2721051, and rs1324183 (p-value < 0.05). The rare variants rs1043208782 and rs569248712 were found in the COL5A1 promoter in two out of 94 rs1536482+ keratoconus patients. Conclusion rs1536482, rs2721051, and rs1324183 were associated with keratoconus in a Russian cohort. SNVs in the COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

scholarly journals In vitro zinc supplementation alters synaptic deficits caused by autism spectrum disorder-associated Shank2 point mutations in hippocampal neurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yukti Vyas ◽  
Yewon Jung ◽  
Kevin Lee ◽  
Craig C. Garner ◽  
Johanna M. Montgomery
Keyword(s):  
Hippocampal Neurons ◽  
Fluorescent Protein ◽  
Zinc Supplementation ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Green Fluorescent ◽  
The Impact

AbstractAutism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterised by deficits in social interactions and repetitive behaviours. ASDs have a strong genetic basis with mutations involved in the development and function of neural circuitry. Shank proteins act as master regulators of excitatory glutamatergic synapses, and Shank mutations have been identified in people with ASD. Here, we have investigated the impact of ASD-associated Shank2 single nucleotide variants (SNVs) at the synaptic level, and the potential of in vitro zinc supplementation to prevent synaptic deficits. Dissociated rat hippocampal cultures expressing enhanced green fluorescent protein (EGFP) tagged Shank2-Wildtype (WT), and ASD-associated Shank2 single nucleotide variants (SNVs: S557N, V717F, and L1722P), were cultured in the absence or presence of 10 μM zinc. In comparison to Shank2-WT, ASD-associated Shank2 SNVs induced significant decreases in synaptic density and reduced the frequency of miniature excitatory postsynaptic currents. These structural and functional ASD-associated synaptic deficits were prevented by chronic zinc supplementation and further support zinc supplementation as a therapeutic target in ASD.

scholarly journals Quantification of autism recurrence risk by direct assessment of paternal sperm mosaicism

2017 ◽  
Author(s):  
Martin W. Breuss ◽  
Morgan Kleiber ◽  
Renee D. George ◽  
Danny Antaki ◽  
Kiely N. James ◽  
...  
Keyword(s):  
Single Molecule ◽  
De Novo ◽  
Recurrence Risk ◽  
Autism Spectrum ◽  
Causative Mutation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Germline Mosaicism ◽  
Spectrum Disorders ◽  
Low Levels

SummaryDe novo genetic mutations represent a major contributor to pediatric disease, including autism spectrum disorders (ASD), congenital heart disease, and muscular dystrophies1,2, but there are currently no methods to prevent or predict them. These mutations are classically thought to occur either at low levels in progenitor cells or at the time of fertilization1,3 and are often assigned a low risk of recurrence in siblings4,5. Here, we directly assess the presence of de novo mutations in paternal sperm and discover abundant, germline-restricted mosaicism. From a cohort of ASD cases, employing single molecule genotyping, we found that four out of 14 fathers were germline mosaic for a putatively causative mutation transmitted to the affected child. Three of these were enriched or exclusively present in sperm at high allelic fractions (AF; 7-15%); and one was recurrently transmitted to two additional affected children, representing clinically actionable information. Germline mosaicism was further assessed by deep (>90x) whole genome sequencing of four paternal sperm samples, which detected 12/355 transmitted de novo single nucleotide variants that were mosaic above 2% AF, and more than two dozen additional, non-transmitted mosaic variants in paternal sperm. Our results demonstrate that germline mosaicism is an underestimated phenomenon, which has important implications for clinical practice and in understanding the basis of human disease. Genetic analysis of sperm can assess individualized recurrence risk following the birth of a child with a de novo disease, as well as the risk in any male planning to have children.

scholarly journals Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation

2018 ◽  
Vol 19 (4) ◽  
pp. 349-359 ◽  
Author(s):  
Ditte Bjerre ◽  
Henrik Berg Rasmussen ◽  
The INDICES Consortium
Keyword(s):  
Structural Variation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Novel Approach

scholarly journals Multi-Omics Analysis Identifies the Heterogeneity and Prognosis in Bladder Cancer

2021 ◽  
Author(s):  
Wenchao Ma ◽  
Cheng Li ◽  
Yuchao Liu ◽  
Wentao Zhang ◽  
Yadong Guo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
High Risk ◽  
Copy Number ◽  
Low Risk ◽  
Biological Behavior ◽  
Methylation Data ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Risk Patients

Abstract Background The multi-omics integrated analysis can help researchers understand the biological behavior of bladder cancer(BCa) in a more systematic and comprehensive manner, and further provide new clues for finding valuable tumor markers and therapeutic targets. Methods In this study, we applied the DNA methylation data to construct a prognosis classifier and stratified the BCa patients into high- and low-risk subtype. The differences of transcriptome, single nucleotide variants and copy number variations between two subgroups were explored for finding the changes of molecular mechanism. Results With 18 pairs DNA methylation samples, ten differentially methylated positions(DMPs) were identified and applied to evaluate the risk score of each sample. Kaplan-Meier survival analysis displayed that BCa patients with high risk had a poor prognosis than the lower(p<0.0001). In transcriptome analysis, many immune related pathways and biological process changed between high- and low-risk patients. The results also displayed that naive B cells, plasma cells, CD8+ T cells and T cell regulatory(Tregs) infiltrated less in high-risk patients and these patients were less sensitive to immunotherapy and chemotherapy. As for single nucleotide variants, we found that TP53, CDKN1A, STAG2 and other genes were more frequently mutated in high-risk BCa patients. Only copy number variation in high-risk patients were displayed for the limitation of TCGA data. Conclusions The high- and low-risk patients identified by DNA methylation data of bladder cancer were significant different in survival. The comprehensive comparison of multi-omics data between subgroups can help clinicians find the heterogeneity of tumor biological behavior and contribute to precision treatment in bladder cancer.

scholarly journals The Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral Cortex

2020 ◽  
Author(s):  
Rachel E. Rodin ◽  
Yanmei Dou ◽  
Minseok Kwon ◽  
Maxwell A. Sherman ◽  
Alissa M. D’Gama ◽  
...  
Keyword(s):  
Human Brain ◽  
Somatic Mutations ◽  
De Novo ◽  
Germline Mutations ◽  
Autism Spectrum ◽  
Single Nucleotide Variants ◽  
Human Cerebral Cortex ◽  
Single Nucleotide ◽  
Normal Human ◽  
Enhancer Sequences

AbstractAlthough somatic mutations have well-established roles in cancer and certain focal epilepsies, the extent to which mutational mosaicism shapes the developing human brain is poorly understood. Here we characterize the landscape of somatic mutations in the human brain using ultra-deep (~250×) whole-genome sequencing of brains from 59 autism spectrum disorder (ASD) cases and 15 controls. We observe a mean of 26 (±10, range 10-60) somatic single nucleotide variants (sSNVs) per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This rate suggests that a typical individual possesses ~80 sSNVs present in ≥2% of cells—comparable to the number of de novo germline mutations per generation—with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. Although limited by sample size, ASD brains show an excess of somatic mutations in neural enhancer sequences compared to controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.

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