Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction

Abstract Background Epilepsy is one of the most common and heterogeneous neurological diseases. The main clinical signs of the disease are repeated symptomatic or idiopathic epileptic seizures of both convulsive and non-convulsive nature that develop against a background of lost or preserved consciousness. The genetic component plays a large role in the etiology of idiopathic forms of epilepsy. The study of the molecular genetic basis of neurological disorders has led to a rapidly growing number of gene mutations known to be involved in hereditary ion channel dysfunction. The aim of this research was to evaluate the involvement of single-nucleotide variants that modify the function of genes (SCN1A, KCNT1, KCNTС1, and KCNQ2) encoding sodium and potassium ion channel polypeptides in the development of epilepsy. Results De novo mutations in the sodium channel gene SCN1A c.5347G>A (p. Ala1783Thr) were detected in two patients with Dravet syndrome, with a deletion in exon 26 found in one. Three de novo mutations in the potassium channel gene KCNT1 c.2800G>A (p. Ala934Thr), were observed in two patients with temporal lobe epilepsy (TLE) and one patient with residual encephalopathy. Moreover, a control cohort matched to the case cohort did not reveal any SNVs among conditionally healthy individuals, supporting the pathogenic significance of the studied SNVs. Conclusion Our results are supported by literature data showing that the sodium ion channel gene SCN1A c.5347G>A mutation may be involved in the pathogenesis of Dravet syndrome. We also note that the c.2800G>A mutation in the potassium channel gene KCNT1 can cause not only autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) but also other forms of epilepsy. To treat pathogenetic mutations that accelerate the function of sodium and potassium ion channels, we recommend ion channel blockade drug therapy.

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An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

Scientific Reports ◽

10.1038/srep22851 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 9

Author(s):

Leandro de Araújo Lima ◽

Ana Cecília Feio-dos-Santos ◽

Sintia Iole Belangero ◽

Ary Gadelha ◽

Rodrigo Affonseca Bressan ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Integrative Approach ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Hyperactivity Disorder ◽

New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

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Implications of Genetic Distance to Reference and De Novo Genome Assembly for Clinical Genomics in Africans

10.1101/2020.09.25.20201780 ◽

2020 ◽

Author(s):

Daniel Shriner ◽

Adebowale Adeyemo ◽

Charles Rotimi

Keyword(s):

Genetic Distance ◽

De Novo ◽

Reference Sequence ◽

Sequencing Data ◽

Single Nucleotide Variants ◽

De Novo Genome Assembly ◽

Single Nucleotide ◽

Clinical Genomics ◽

Advantages And Disadvantages ◽

False Discovery

In clinical genomics, variant calling from short-read sequencing data typically relies on a pan-genomic, universal human reference sequence. A major limitation of this approach is that the number of reads that incorrectly map or fail to map increase as the reads diverge from the reference sequence. In the context of genome sequencing of genetically diverse Africans, we investigate the advantages and disadvantages of using a de novo assembly of the read data as the reference sequence in single sample calling. Conditional on sufficient read depth, the alignment-based and assembly-based approaches yielded comparable sensitivity and false discovery rates for single nucleotide variants when benchmarked against a gold standard call set. The alignment-based approach yielded coverage of an additional 270.8 Mb over which sensitivity was lower and the false discovery rate was higher. Although both approaches detected and missed clinically relevant variants, the assembly-based approach identified more such variants than the alignment-based approach. Of particular relevance to individuals of African descent, the assembly-based approach identified four heterozygous genotypes containing the sickle allele whereas the alignment-based approach identified no occurrences of the sickle allele. Variant annotation using dbSNP and gnomAD identified systematic biases in these databases due to underrepresentation of Africans. Using the counts of homozygous alternate genotypes from the alignment-based approach as a measure of genetic distance to the reference sequence GRCh38.p12, we found that the numbers of misassemblies, total variant sites, potentially novel single nucleotide variants (SNVs), and certain variant classes (e.g., splice acceptor variants, stop loss variants, missense variants, synonymous variants, and variants absent from gnomAD) were significantly correlated with genetic distance. In contrast, genomic coverage and other variant classes (e.g., ClinVar pathogenic or likely pathogenic variants, start loss variants, stop gain variants, splice donor variants, incomplete terminal codons, variants with CADD score ≥20) were not correlated with genetic distance. With improvement in coverage, the assembly-based approach can offer a viable alternative to the alignment-based approach, with the advantage that it can obviate the need to generate diverse human reference sequences or collections of alternate scaffolds.

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Recent Advances in Understanding the Genetic Architecture of Autism

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-121219-082309 ◽

2020 ◽

Vol 21 (1) ◽

pp. 289-304 ◽

Cited By ~ 1

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.

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Haplotype-aware variant calling enables high accuracy in nanopore long-reads using deep neural networks

10.1101/2021.03.04.433952 ◽

2021 ◽

Author(s):

Kishwar Shafin ◽

Trevor Pesout ◽

Pi-Chuan Chang ◽

Maria Nattestad ◽

Alexey Kolesnikov ◽

...

Keyword(s):

De Novo ◽

Sequence Data ◽

Variant Calling ◽

High Accuracy ◽

Superior Performance ◽

Read Length ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Short Read ◽

Long Read

Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read based phasing. Third-generation nanopore sequence data has demonstrated a long read length, but current interpretation methods for its novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline PEPPER-Margin-DeepVariant that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single nucleotide variant identification method at the whole genome-scale and produces high-quality single nucleotide variants in segmental duplications and low-mappability regions where short-read based genotyping fails. We show that our pipeline can provide highly-contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% to 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance than the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio-HiFi-polished).

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Fast neutron mutagenesis in soybean enriches for small indels and creates frameshift mutations

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkab431 ◽

2021 ◽

Author(s):

Skylar R Wyant ◽

M Fernanda Rodriguez ◽

Corey K Carter ◽

Wayne A Parrott ◽

Scott A Jackson ◽

...

Keyword(s):

Fast Neutron ◽

De Novo ◽

Spontaneous Mutation ◽

Local Context ◽

Induced Mutations ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Frameshift Mutations ◽

Small Indels ◽

Standing Variation

Abstract The mutagenic effects of ionizing radiation have been used for decades to create novel variants in experimental populations. Fast neutron (FN) bombardment as a mutagen has been especially widespread in plants, with extensive reports describing the induction of large structural variants, i.e., deletions, insertions, inversions, and translocations. However, the full spectrum of FN-induced mutations is poorly understood. We contrast small insertions and deletions (indels) observed in 27 soybean lines subject to FN irradiation with the standing indels identified in 107 diverse soybean lines. We use the same populations to contrast the nature and context (bases flanking a nucleotide change) of single nucleotide variants. The accumulation of new single nucleotide changes in FN lines is marginally higher than expected based on spontaneous mutation. In FN treated lines and in standing variation, C→T transitions and the corresponding reverse complement G→A transitions are the most abundant and occur most frequently in a CpG local context. These data indicate that most SNPs identified in FN lines are likely derived from spontaneous de novo processes in generations following mutagenesis rather than from the FN irradiation mutagen. However, small indels in FN lines differ from standing variants. Short insertions, from 1–6 base pairs, are less abundant than in standing variation. Short deletions are more abundant and prone to induce frameshift mutations that should disrupt the structure and function of encoded proteins. These findings indicate that FN irradiation generates numerous small indels, increasing the abundance of loss of function mutations that impact single genes.

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From the periphery to centre stage: de novo single nucleotide variants play a key role in human genetic disease

Journal of Medical Genetics ◽

10.1136/jmedgenet-2013-101519 ◽

2013 ◽

Vol 50 (4) ◽

pp. 203-211 ◽

Cited By ~ 27

Author(s):

Chee-Seng Ku ◽

Eng King Tan ◽

David N Cooper

Keyword(s):

Genetic Disease ◽

De Novo ◽

Single Nucleotide Variants ◽

Human Genetic Disease ◽

Single Nucleotide

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Genome-wide DNA mutations in Arabidopsis plants after multigenerational exposure to high temperatures

Genome Biology ◽

10.1186/s13059-021-02381-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhaogeng Lu ◽

Jiawen Cui ◽

Li Wang ◽

Nianjun Teng ◽

Shoudong Zhang ◽

...

Keyword(s):

Tandem Repeats ◽

Elevated Temperatures ◽

De Novo ◽

Biological Evolution ◽

Distribution Patterns ◽

Defense Responses ◽

Plant Evolution ◽

De Novo Mutations ◽

Single Nucleotide Variants ◽

Dna Mutations

Abstract Background Elevated temperatures can cause physiological, biochemical, and molecular responses in plants that can greatly affect their growth and development. Mutations are the most fundamental force driving biological evolution. However, how long-term elevations in temperature influence the accumulation of mutations in plants remains unknown. Results Multigenerational exposure of Arabidopsis MA (mutation accumulation) lines and MA populations to extreme heat and moderate warming results in significantly increased mutation rates in single-nucleotide variants (SNVs) and small indels. We observe distinctive mutational spectra under extreme and moderately elevated temperatures, with significant increases in transition and transversion frequencies. Mutation occurs more frequently in intergenic regions, coding regions, and transposable elements in plants grown under elevated temperatures. At elevated temperatures, more mutations accumulate in genes associated with defense responses, DNA repair, and signaling. Notably, the distribution patterns of mutations among all progeny differ between MA populations and MA lines, suggesting that stronger selection effects occurred in populations. Methylation is observed more frequently at mutation sites, indicating its contribution to the mutation process at elevated temperatures. Mutations occurring within the same genome under elevated temperatures are significantly biased toward low gene density regions, special trinucleotides, tandem repeats, and adjacent simple repeats. Additionally, mutations found in all progeny overlap significantly with genetic variations reported in 1001 Genomes, suggesting non-uniform distribution of de novo mutations through the genome. Conclusion Collectively, our results suggest that elevated temperatures can accelerate the accumulation, and alter the molecular profiles, of DNA mutations in plants, thus providing significant insight into how environmental temperatures fuel plant evolution.

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A fully phased accurate assembly of an individual human genome

10.1101/855049 ◽

2019 ◽

Cited By ~ 19

Author(s):

David Porubsky ◽

Peter Ebert ◽

Peter A. Audano ◽

Mitchell R. Vollger ◽

William T. Harvey ◽

...

Keyword(s):

Genome Assembly ◽

De Novo ◽

Consensus Sequence ◽

Error Rates ◽

Single Individual ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Consensus Sequences ◽

Oxford Nanopore ◽

Genome Assemblies

The prevailing genome assembly paradigm is to produce consensus sequences that “collapse” parental haplotypes into a consensus sequence. Here, we leverage the chromosome-wide phasing and scaffolding capabilities of single-cell strand sequencing (Strand-seq)1,2 and combine them with high-fidelity (HiFi) long sequencing reads3, in a novel reference-free workflow for diploid de novo genome assembly. Employing this strategy, we produce completely phased de novo genome assemblies separately for each haplotype of a single individual of Puerto Rican origin (HG00733) in the absence of parental data. The assemblies are accurate (QV > 40), highly contiguous (contig N50 > 25 Mbp) with low switch error rates (0.4%) providing fully phased single-nucleotide variants (SNVs), indels, and structural variants (SVs). A comparison of Oxford Nanopore and PacBio phased assemblies identifies 150 regions that are preferential sites of contig breaks irrespective of sequencing technology or phasing algorithms.

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Genetics of Schizophrenia and Bipolar Disorder

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0018 ◽

2013 ◽

pp. 232-246 ◽

Cited By ~ 1

Author(s):

Pamela Sklar

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychotic Disorders ◽

De Novo ◽

Copy Number Variants ◽

Nucleotide Polymorphisms ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Sequencing Studies ◽

Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. The explosion of strong and convincing genetic evidence indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. There is a role for rare single nucleotide variation as well as de novo genetic variation being pointed to in new sequencing studies, but their overall contribution to risk is less clear. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, there is evidence for polygenicity and as yet no deep sequencing surveys have been published. Several intriguing biological pathways are suggested by these genetic findings related to microRNAs and calcium channel signaling. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder. Translating these results into biological and etiological understanding has not yet advanced, and will likely only do so when experimental methods are developed than can address the large numbers of genes and variants within them that, along with environmental and stochastic effects, result in the development of disease for a particular person.

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