Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice

Scheffer, Ingrid E.; Bennett, Caitlin A.; Gill, Deepak; Silva, Michelle G. de; Boggs, Kirsten; Marum, Justine E; Baker, Naomi L.; Palmer, Elizabeth E.; Howell, Katherine; Andrews, Ian; Antony, Jayne; Ardern‐Holmes, Simone; Bye, Ann; Cardamone, Michael; Chelakkadan, Shabeed; Clark, Damian; Curnow, Sarah R; Dabscheck, Gabriel; Fahey, Michael; Freeman, Jeremy L.; Gupta, Sachin; Harvey, A. Simon; Hildebrand, Michael S.; Inder, Marie K.; Kanhangad, Manoj; Kornberg, Andrew J.; Kothur, Kavitha; Lawson, John A.; Leventer, Richard J.; Malone, Stephen M.; Menezes, Manoj P.; Mohammad, Shekeeb S; Nagarajan, Lakshmi; Pillai, Supriya; Pridmore, Clair; Procopis, Peter G.; Sampaio, Hugo; Silberstein, Jonathon; Sinclair, Adriane; Smith, Nicholas H.; Subramanian, Gopinath; Troedson, Christopher; Ware, Tyson L; White, Susan

doi:10.1111/dmcn.15308

Cited by 18 publications

(11 citation statements)

References 33 publications

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“…An additional 146 analytical controls (60% female) were included for validation. Individuals with DEEs were recruited from investigators’ research and clinical programs 21,22 . Methylation array data for healthy controls were drawn from a public database 23 (n=111), an internal institutional database (n=337), and 30 unaffected parents of probands with DEEs (Supplemental Methods).…”

Section: Methodsmentioning

confidence: 99%

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

LaFlamme,

Rastin,

Sengupta

et al. 2023

Preprint

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Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations (“epivariants”) can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct “episignature” biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature forCHD2using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights intoCHD2pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.

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Section: Methodsmentioning

confidence: 99%

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

LaFlamme,

Rastin,

Sengupta

et al. 2023

Preprint

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“…1 With advances in next-generation sequencing, the genetic basis is determined in almost 40%–50% of DEEs with more than 800 DEE genes identified. 2-4 These genes implicate a wide range of neurobiological processes. 5,6…”

Section: Introductionmentioning

confidence: 99%

“…1 With advances in next-generation sequencing, the genetic basis is determined in almost 40%-50% of DEEs with more than 800 DEE genes identified. [2][3][4] These genes implicate a wide range of neurobiological processes. 5,6 As larger cohorts of patients with a specific genetic DEE are identified, a phenotypic spectrum typically emerges.…”

Section: Introductionmentioning

confidence: 99%

Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies

van der Veen,

Tse,

Ferretti

et al. 2023

Neurology

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Background and Objectives: Movement disorders are underrecognized in the developmental and epileptic encephalopathies (DEEs). There are now over 800 genes implicated in causing the DEEs; relatively few of these rare genetic diseases are known to be associated with movement disorders. We identified patients with genetic DEEs who had movement disorders, classified the nature of their movement disorders and asked whether specific patterns correlated with the underlying mechanism. Methods: We classified the type of movement disorders associated with specific genetic DEEs in a large international cohort of patients and analysed whether specific patterns of movement disorders reflected the underlying biological dysfunction. Results: Our cohort comprised 77 patients with a genetic DEE with a median age of 9 (range 1-38) years. Stereotypies (37/77, 48%) and dystonia (34/77, 44%) were the most frequent movement disorders, followed by chorea (18/77, 23%), myoclonus (14/77, 18%), ataxia (9/77, 12%), tremor (7/77, 9%) and hypokinesia (6/77, 8%). In 47% of patients, a combination of movement disorders was seen. The movement disorders were first observed at a median age of 18 months (range day 2 - 35 years). Dystonia was more likely to be observed in non-ambulatory patients, while ataxia was less likely. In 46% of patients, therapy was initiated with medication (34/77, 44%), DBS (1/77, 1%), or intrathecal baclofen (1/77, 1%). We found that patients with channelopathies or synaptic vesicle trafficking defects were more likely to have dystonia; whereas, stereotypies were most frequent in individuals with transcriptional defects. Discussion: Movement disorders are often underrecognized in patients with genetic DEEs but recognition is critical for the management of these complex neurological diseases. Distinguishing movement disorders from epileptic seizures is important in tailoring patient treatment. Understanding which movement disorders occur with different biological mechsnisms will inform early diagnosis and management.

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“…Here, we report functional analysis of two unstudied HCN1 variants, together with re-analysis of five variants with some published functional data. 10–12 , 16–18 All pathogenic variants were in the transmembrane domains of the HCN1 protein. A cation leak was established for all, suggesting that there is a common pathogenic mechanism underlying a subset of HCN1 epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy

McKenzie

Forster

Soh

et al. 2023

Brain Communications

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Pathogenic variants in HCN1 are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with HCN1-DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different de novo HCN1 pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven HCN1 pathogenic variants were assessed using two-electrode voltage-clamp recordings in Xenopus oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in HCN1-DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak. Stratification of patients based on their ‘cation leak’ biophysical phenotype may therefore provide key information to guide clinical management of individuals with HCN1-DEE.

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Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice

Cited by 18 publications

References 33 publications

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy

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