Epilepsy and developmental disorders: Next generation sequencing in the clinic

European Journal of Paediatric Neurology, Journal Year: 2019, Volume and Issue: 24, P. 15 - 23

Published: Dec. 18, 2019

Language: Английский

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Developmental and epileptic encephalopathies: what we do and do not know

Brain, Journal Year: 2020, Volume and Issue: 144(1), P. 32 - 43

Published: Oct. 6, 2020

Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an assumed causal relationship between epilepsy developmental delay. encephalopathies pathogenesis more independent from supported by the identification of several gene variants both epilepsy, possibility for gene-associated without continued development even when seizures controlled. Hence, 'developmental epileptic encephalopathy' may be a appropriate term than encephalopathy. This update considers best studied illustrative support over Moreover, interaction considered respect influence on treatment decisions. Continued research in genetic testing will increase access clinical tests, earlier diagnosis, better application current treatments, potentially provide new molecular-investigated treatments.

Language: Английский

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A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

Brain, Journal Year: 2020, Volume and Issue: 143(4), P. 1099 - 1105

Published: Feb. 4, 2020

Abstract A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates not available for the vast majority these monogenic because phenotypic heterogeneity absence large-scale genomic screens. Yet, knowledge incidence is important clinicians researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data predict, first time, incidences 101 known variant-associated as well 3106 putative disorders. Two corroboration analyses supported validity calculated estimates. First, greater predicted gene-disorder positively correlated with larger numbers pathogenic variants collected from patient variant databases (Kendall’s τ = 0.093, P-value 6.9 × 10−6). Second, six seven (86%) associated which epidemiological were (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, CDKL5), matched reported We conclude that in data, our catalogue 3207 can advocacy groups, clinicians, researchers, policymakers strategic decision-making.

Language: Английский

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Genetic testing for the epilepsies: A systematic review

Epilepsia, Journal Year: 2021, Volume and Issue: 63(2), P. 375 - 387

Published: Dec. 10, 2021

Abstract Objective Numerous genetic testing options for individuals with epilepsy have emerged over the past decade without clear guidelines regarding optimal strategies. We performed a systematic evidence review (SER) and conducted meta‐analyses of diagnostic yield tests commonly utilized patients epilepsy. also assessed nonyield outcomes (NYOs) such as changes in treatment and/or management, prognostic information, recurrence risk determination, counseling. Methods an SER, accordance PRISMA (Preferred Reporting Items Systematic Reviews Meta‐Analyses), using PubMed, Embase, CINAHL, Cochrane Central through December 2020. included studies that genome sequencing (GS), exome (ES), multigene panel (MGP), genome‐wide comparative genomic hybridization/chromosomal microarray (CGH/CMA) cohorts ( n ≥ 10) ascertained Quality assessment was undertaken ROBINS‐I (Risk Bias Non‐Randomized Studies Interventions). estimated yields 95% confidence intervals random effects narratively synthesized NYOs. Results From 5985 nonduplicated articles published 2020, 154 met inclusion criteria were yield; 43 those NYO synthesis. The overall across all test modalities 17%, highest GS (48%), followed by ES (24%), MGP (19%), CGH/CMA (9%). only phenotypic factors significantly associated increased (1) presence developmental epileptic encephalopathy (2) neurodevelopmental comorbidities. reporting NYOs addressed clinical personal utility testing. Significance This comprehensive focused specifically on literature epilepsy, provides clinically available tests, which will help shape clinician decision‐making policy insurance coverage highlight need prospective standardization patient characteristics.

Language: Английский

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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Epilepsia, Journal Year: 2020, Volume and Issue: 61(3), P. 387 - 399

Published: Feb. 23, 2020

Abstract Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes neurodevelopmental disorders. To better understand biology of seizure susceptibility ‐related epilepsies, our aim was to determine similarities differences between channel disorders, allowing us develop a broader perspective on precision treatment than an individual gene level alone. Methods We analyzed genotype‐phenotype correlations large ‐patient cohorts applied variant constraint analysis identify severe disease. examined temporal patterns expression correlated functional data from vitro studies clinical across different Results Comparing 865 patients (504 SCN1A , 140 SCN2A 171 SCN8A SCN3A 46 copy number variation [CNV] cases) 114 allowed common presentation. All epilepsy‐associated demonstrated significant both protein truncating missense when compared other genes. observed that age at onset is related over time. Individuals gain‐of‐function SCN2A/3A/8A or CNV duplications characteristics, most frequently present early (<3 months), demonstrate good response blockers (SCBs). Direct comparison corresponding subtypes illustrates effects locations are similar; however, their manifestation differs, depending role types neurons which they expressed. Significance Variant function location within one can serve as surrogate for channels. Taking view suggests those suspected underlying genetic presenting neonatal seizures SCBs should be considered.

Language: Английский

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“The First Thousand Days” Define a Fetal/Neonatal Neurology Program

Frontiers in Pediatrics, Journal Year: 2021, Volume and Issue: 9

Published: Aug. 2, 2021

Gene–environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the (MPF) triad, expressed as malformations destructive lesions. Maladaptive MPF triad impair progenitor neuronal/glial populations within transient embryonic/fetal structures by processes such maternal immune activation. Destructive fetal lesions later in pregnancy result from ischemic placental syndromes associated great obstetrical syndromes. Trimester-specific diseases may negatively impact labor delivery outcomes. Neonatal neurocritical care addresses symptomatic minority who express neonatal neurological syndromes: encephalopathy, seizures, stroke, encephalopathy prematurity. The asymptomatic majority present neurologic disorders before 2 years age without prior detection. principle ontogenetic adaptation helps guide diagnostic process days identify phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, research agenda among multiple FNNP. Effective early-life programs help reduce disease burden across lifespan successive generations.

Language: Английский

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Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Genes, Journal Year: 2021, Volume and Issue: 12(7), P. 1051 - 1051

Published: July 8, 2021

The high pace of gene discovery has resulted in thrilling advances the field epilepsy genetics. Clinical testing with comprehensive panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield early-onset epilepsies enabled precision medicine approaches. These been instrumental providing insights into pathophysiology both benign self-limited syndromes devastating developmental epileptic encephalopathies (DEEs). Genetic heterogeneity is seen many such as West syndrome infancy migrating focal seizures (EIMFS), indicating that two more genetic loci produce same similar phenotypes. At time, some genes SCN2A can be associated wide range ranging from familial neonatal at mild end Ohtahara syndrome, EIFMS, Lennox–Gastaut unclassifiable DEEs severe spectrum. aim this study was review clinical starting first year life including: Self-limited neonatal, neonatal-infantile infantile epilepsies, febrile plus spectrum, myoclonic infancy, early encephalopathy, Dravet EIMFS, DEEs. We also elaborate on advantages pitfalls conditions. Finally, we describe how diagnosis potentially enable therapy monogenic emphasize cornerstone for therapeutic strategies.

Language: Английский

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Utility of genetic testing for therapeutic decision‐making in adults with epilepsy

Epilepsia, Journal Year: 2020, Volume and Issue: 61(6), P. 1234 - 1239

Published: May 19, 2020

Genetic testing has become a routine part of the diagnostic workup in children with early onset epilepsies. In present study, we sought to investigate cohort adult patients epilepsy, determinate yield and explore gain personalized treatment approaches patients.Two hundred (age span = 18-80 years) referred for gene panel at Danish Epilepsy Center were included. The vast majority (91%) suffered from comorbid intellectual disability. medical records genetically diagnosed mined data on epilepsy syndrome, cognition, changes, seizure outcome following genetic diagnosis.We found diagnosis 46 200 (23%) patients. SCN1A, KCNT1, STXBP1 accounted greatest number positive findings (48%). More rare included SLC2A1, ATP6A1V, HNRNPU, MEF2C, IRF2BPL. Gene-specific changes initiated 11 (17%) (one 10 SCN1A) diagnosis. Ten improved, reduction and/or increased alertness general well-being.With this show that is highly relevant adults epilepsy. similar previously reported pediatric cohorts, can be useful therapeutic decision-making, which may lead better control, ultimately improving quality life.

Language: Английский

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Current practice in diagnostic genetic testing of the epilepsies

Epileptic Disorders, Journal Year: 2022, Volume and Issue: 24(5), P. 765 - 786

Published: July 13, 2022

Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances genomic knowledge analysis platforms have begun to make clinical genetic testing accessible for, principle, people of all ages epilepsy. For this reason, Genetics Commission International League Against (ILAE) presents update on practice, including current techniques, indications, yield testing, recommendations for pre- post-test counseling, follow-up after completed. We acknowledge that resources vary across different settings but highlight diagnostic epilepsy should be prioritized when likelihood an informative finding high. Results particular identification causative variants, likely improve individual care. emphasize importance individuals as we enter era therapy.

Language: Английский

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Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel

Neuron, Journal Year: 2021, Volume and Issue: 110(2), P. 237 - 247.e4

Published: Nov. 11, 2021

Language: Английский

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