Chromosomal microarray in unexplained severe early onset epilepsy – A single centre cohort

Allen, Nicholas M.; Conroy, Judith; Shahwan, Amre; Ennis, Sean; Lynch, Bryan; Lynch, Sally Ann; King, Mary D.

doi:10.1016/j.ejpn.2015.03.010

Cited by 14 publications

(13 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This number reaches 12.7% when we also consider the possibly pathogenic CNVs. Previous similar studies report a diagnostic yield ranging from ~5% to 12% . Thus, our result fits at the upper limit of this range, probably mainly due to the “epilepsy plus” phenotype of our cohort and to the application of a standardized workflow.…”

Section: Discussionsupporting

confidence: 82%

“…The maximum frequency of pathogenic CNVs reported in any of these series was 12%, with a range of 5%‐12%. These studies tended to focus on individuals who were children at the time of testing . The importance of rare CNVs has been well recognized in patients with neuropsychiatric disorders including unexplained ID, congenital anomalies, and seizures.…”

Section: Discussionmentioning

confidence: 99%

“…However, CNVs may be seen in healthy control individuals, and determination of the pathogenicity of newly identified CNVs can be challenging. To evaluate the role of pathogenic CNVs and identify possible candidate genes, we investigated the occurrence of CNVs in epilepsy plus, in a cohort among the largest reported to date . Data were collected from eight centers and included both adults and children.…”

Section: Discussionmentioning

confidence: 99%

“…Whole genome oligonucleotide array CGH or SNP array is routinely included in evaluation of patients with complex phenotypes with a suspected genetic cause . CNVs, as a risk factor or cause, have been reported in ~5%‐12% of patients with different types of epilepsies . The risk of a pathogenic CNV is reportedly increased with concurrent intellectual disability (ID), dysmorphic features, autism spectrum disorder (ASD), drug resistance, or other comorbidities, from a study of 222 patients .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

View full text Add to dashboard Cite

Summary Objective Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Targeted testing should be performed in infants in whom a metabolic diagnosis is strongly suspected and in subgroups with higher likelihood of treatable metabolic conditions, such as neonates and parental consanguinity . Although not modeled here, the yield of first‐tier metabolic testing and chromosomal microarray probably warrants their continued use …”

Section: Discussionmentioning

confidence: 99%

A population‐based cost‐effectiveness study of early genetic testing in severe epilepsies of infancy

et al. 2018

View full text Add to dashboard Cite

show abstract

Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes

Patel

Mercimek-Mahmutoglu

2016

Indian J Pediatr

View full text Add to dashboard Cite

Epilepsy is one of the most common neurological disorders in childhood. Epilepsy associated with global developmental delay and cognitive dysfunction is defined as epileptic encephalopathy. Certain inherited metabolic disorders presenting with epileptic encephalopathy can be treated with disease specific diet, vitamin, amino acid or cofactor supplementations. In those disorders, disease specific therapy is successful to achieve good seizure control and improve long-term neurodevelopmental outcome. For this reason, intractable epilepsy with global developmental delay or history of developmental regression warrants detailed metabolic investigations for the possibility of an underlying treatable inherited metabolic disorder, which should be undertaken as first line investigations. An underlying genetic etiology in epileptic encephalopathy has been supported by recent studies such as array comparative genomic hybridization, targeted next generation sequencing panels, whole exome and whole genome sequencing. These studies report a diagnostic yield up to 70%, depending on the applied genetic testing as well as number of patients enrolled. In patients with epileptic encephalopathy, a stepwise approach for diagnostic work-up will help to diagnose treatable inherited metabolic disorders quickly. Application of detailed genetic investigations such as targeted next generation sequencing as second line and whole exome sequencing as third line testing will diagnose underlying genetic disease which will help for genetic counseling as well as guide for prenatal diagnosis. Knowledge of underlying genetic cause will provide novel insights into the pathogenesis of epileptic encephalopathy and pave the ground towards the development of targeted neuroprotective treatment strategies to improve the health outcome of children with epileptic encephalopathy.

show abstract

Chromosomal microarray in unexplained severe early onset epilepsy – A single centre cohort

Cited by 14 publications

References 17 publications

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic implications of genetic copy number variation in epilepsy plus

A population‐based cost‐effectiveness study of early genetic testing in severe epilepsies of infancy

Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes

Contact Info

Product

Resources

About