dbVar and DGVa: public archives for genomic structural variation

Lappalainen, Ilkka; Lopez, John; Skipper, Lisa; Hefferon, Timothy; Spalding, J. Dylan; Garner, John; Chen, Chao; Maguire, Michael E.; Corbett, Matthew J.; Zhou, George; Paschall, Justin; Ananiev, Victor; Flicek, Paul; Church, Deanna M.

doi:10.1093/nar/gks1213

Cited by 247 publications

(222 citation statements)

References 21 publications

(17 reference statements)

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“…Variant information was gathered from population databases (Exome Aggregation Consortium 14 , Exome Variant server 15 , 1000 Genomes 16 , dbSNP 17 and dbVAR 18 ), disease databases (humsavar.txt release 2016_05 19 , ClinVar 20 , HGMD-public 21 , OMIM 22 and OMIA 23 ) and sequence databases (RefSeqGene 24 , NCBI Genome 25 , UCSC Genome 26 and Ensembl Genome 27 ). I-Mutant2.0 28 was used as a predictor of protein stability changes upon variations.…”

Section: Bioinformatics Tools For Sequence Variant Interpretationmentioning

confidence: 99%

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

et al. 2016

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SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T4C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/ phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.

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Section: Bioinformatics Tools For Sequence Variant Interpretationmentioning

confidence: 99%

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

et al. 2016

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“…26 The Database of Genomic Structural Variation (dbVar) hosts 106 published studies, including 85 human, 12 mouse, and several other animal datasets (http://www.ncbi.nlm.nih.gov/dbvar/). 27,28 Different CNV detection platforms (hybridization or sequence based) and calling algorithms resulted in different CNV datasets in varying resolution. 29 Several major CNV formation mechanisms have been proposed, including NAHR (Non-Allelic Homologous Recombination), NHEJ (Non-Homologous End Joining), MEI (Mobile Element Insertion), and FoSTeS/MMBIR (Fork Stalling and Template Switching and Microhomology-Mediated Break-Induced Replication).…”

Section: Cnvs In Human and Model Organismsmentioning

confidence: 99%

Recent Advances in Studying of Copy Number Variation and Gene Expression

Liu¹,

Xu²,

Huang³

2014

GGG

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Copy number variations (CNVs) are gains and losses of genomic sequence between two individuals of a species. CNV can have a significant impact on the expression of genes mapped within, nearby and far away from the CNV event itself. Earlier studies have revealed that CNV effects can be caused by affecting gene dosage, through position effect, altering downstream pathways and regulatory networks, or modifying the chromosome structure and position within the nucleus. We will first review recently published results based on high-resolution CNV and transcriptome data. We will then discuss new insights brought by emerging new technologies of next generation sequencing and single-cell sequencing.

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“…The Sequence Ontology variant effect terms have been created in collaboration with Ensembl, and many variant annotation tools 23,24,25 have adopted them. The common terminology that the Sequence Ontology provides for describing variant effects enables the comparison of annotations across tools, and Sequence Ontology terms are used by most genetic variant databases, such as ClinVar, dbVar, dbSNP and Ensembl Variation 17,28–30 .…”

Section: Describing Variantsmentioning

confidence: 99%

Settling the score: variant prioritization and Mendelian disease

2017

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When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype–phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing.

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dbVar and DGVa: public archives for genomic structural variation

Cited by 247 publications

References 21 publications

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

Recent Advances in Studying of Copy Number Variation and Gene Expression

Settling the score: variant prioritization and Mendelian disease

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