Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Allen, Andrew S.; Coe, Bradley P.; Cook, Joseph; Cossette, Patrick; Delanty, Norman; Eichler, Evan E.; Goldstein, David B.; Heinzen, Erin L.; Johnson, Michael R.; Krumm, Nik; Marson, Anthony G; Mefford, Heather C; Nelson, Ben; Nieh, Sahar Esmaeeli; O’Brien, Terence J.; Petrou, Stephen; Petrovski, Slavé; Raja, Archana; Ruzzo, Elizabeth K.; Abou‐Khalil, Bassel; Alldredge, Brian K.; Andermann, Eva; Andermann, Frédérick; Amron, Dina; Bautista, Jocelyn F.; Berkovic, Samuel F.; Boro, Alex; Cascino, Gregory D.; Consalvo, D.; Crumrine, Patricia K.; Devinsky, Orrin; Dlugos, Dennis J.; Epstein, Michael P.; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel J.; Geller, Eric B.; Glauser, Tracy A.; Glynn, Simon; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta M.; Kanner, Andrés M.; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H.; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H.; McGuire, Shannon M.; Motika, Paul; Novotny, Edward J.; Ottman, Ruth; Paolicchi, Juliann; Parent, Jack M.; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E.; Shellhaas, Renée A.; Sherr, Elliott H.; Shih, Jerry J.; Singh, Rani K.; Sirven, Joseph; Smith, Michael C.; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P.G.; Allmen, Gretchen K. Von; Weisenberg, Judith; Widdess‐Walsh, Peter; Winawer, Melodie R.

doi:10.1002/ana.24457

Cited by 56 publications

(26 citation statements)

References 22 publications

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“…Due to the relatively small samples sizes of studies investigating de novo CNVs in other disorders, we did not test the significance of overlap between de novo CNVs in TD and other conditions. However, we did observe de novo CNVs in TD cases that have also been detected in other disorders ( Table S3 ), for example, CNVs in 15q13.2–13.3 have been observed in ASD ( Sanders et al, 2015 ), schizophrenia ( Georgieva et al, 2014 ; Malhotra et al, 2011 ), and epilepsy ( Epilepsy Phenome/Genome Project Epi4K Consortium, 2015 ).…”

Section: Resultsmentioning

confidence: 51%

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Wang¹,

Mandell²,

Kumar

et al. 2018

Cell Reports

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SUMMARY We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 ( cadherin EGF LAG seven-pass G-type receptor 3 ); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

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Section: Resultsmentioning

confidence: 51%

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Wang¹,

Mandell²,

Kumar

et al. 2018

Cell Reports

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“…The latter is a known risk factor for epilepsy 27 . NIPA1 is not considered a definitive epilepsy gene, yet has accumulating recent evidence for its association with epilepsy 28 – 30 . This analysis implicates these variants as strong epilepsy candidates.…”

Section: Resultsmentioning

confidence: 99%

Annotating pathogenic non-coding variants in genic regions

et al. 2017

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Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.

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“…In addition, there was an excess of large (>2 megabase) rare deletions in cases compared to controls. In the EEs, pathogenic CNVs account for approximately 3–5 % of cases [ 11 , 26 ]. Interestingly, deletions of 15q13.3, 15q11.2 and 16p13.11, important for GGE and focal epilepsy, are rarely seen in patients with EE, highlighting the notion that the major classes of epilepsy have different genetic architectures [ 27 ].…”

Section: Copy Number Variants In Epilepsymentioning

confidence: 99%

Advancing epilepsy genetics in the genomic era

Myers¹,

Mefford²

2015

Genome Med

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184

151

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Epilepsy is a group of disorders characterized by recurrent seizures, and is one of the most common neurological conditions. The genetic basis of epilepsy is clear from epidemiological studies and from rare gene discoveries in large families. The three major classes of epilepsy disorders are genetic generalized, focal and encephalopathic epilepsies, with several specific disorders within each class. Advances in genomic technologies that facilitate genome-wide discovery of both common and rare variants have led to a rapid increase in our understanding of epilepsy genetics. Copy number variant and genome-wide association studies have contributed to our understanding of the complex genetic architecture of generalized epilepsy, while genetic insights into the focal epilepsies and epileptic encephalopathies have come primarily from exome sequencing. It is increasingly clear that epilepsy is genetically heterogeneous, and novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation and regulation of the mammalian target of rapamycin (mTOR) protein in the etiology of epilepsy. Such discoveries pave the way for new therapeutics, some of which are already being studied. In this review, we discuss the rapid pace of gene discovery in epilepsy, as facilitated by genomic technologies, and highlight several novel genes and potential therapies.

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Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Cited by 56 publications

References 22 publications

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Annotating pathogenic non-coding variants in genic regions

Advancing epilepsy genetics in the genomic era

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