Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy

Gürsoy, Semra; Erçal, Derya

doi:10.1177/0883073815599262

Cited by 67 publications

(51 citation statements)

References 95 publications

(143 reference statements)

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“…In addition, the field is rapidly changing. OMIM currently lists 56 genetic causes of infantile onset EE (source: Online Mendelian Inheritance in Man website accessed June 2017, http://www.omim.org/phenotypicSeries/PS308350), but there are well over 200 monogenetic conditions in which EE has been reported (Gursoy & Ercal, ). However, there is now a substantial body of work demonstrating that application of high‐throughput sequencing (HTS) via targeted multigene panels or exome sequencing (ES) improves diagnostic yield in EE by 20%–40% (Chambers, Jansen, & Dhamija, ; Consortium E‐R, Project EPG, Consortium EK, ; Helbig et al., ; Kwong et al., ; Lemke et al., ; Trump et al., ); HTS has the potential to minimize this invasive and expensive “diagnostic odyssey.” Most reports claim that this implies cost effectiveness (Helbig et al., ; Lemke et al., ), but solid health economic data are lacking.…”

Section: Introductionmentioning

confidence: 99%

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Palmer

Schofield

Shrestha

et al. 2018

Molec Gen & Gen Med

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BackgroundEpileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.MethodsWe conducted a retrospective cost‐effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well‐phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first‐tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.ResultsThe diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost‐effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost‐effective. The clinical utility of all diagnoses was reported.ConclusionOur study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.

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Section: Introductionmentioning

confidence: 99%

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Palmer

Schofield

Shrestha

et al. 2018

Molec Gen & Gen Med

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“…Studies in animal models reveal that a reduction in SLC12A5 expression results in an increased susceptibility to the development of seizures: complete deletion of SLC12A5 is incompatible with life, a 95% reduction in SLC12A5 expression results in handling‐induced seizure behavior, and heterozygous animals have a lower threshold for epileptic seizures—electrophysiologic measurements in the hippocampus show hyperexcitability, and animals demonstrate a twofold increase in pentylenetetrazole‐induced seizures . An example of a neurotransmitter transporter is the glutamate transporter SLC25A22 ; mutations in this gene cause various epilepsy syndromes . Further examples of the potential role in epilepsy of the identified SLCs are provided in Data S1.…”

Section: Discussionmentioning

confidence: 99%

An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters

et al. 2016

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SUMMARYObjective: Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource-intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy. Methods: Using our in silico system, we predicted the SLCs likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLCs dysregulated in epileptic foci, and determining the overlap between our in silico and ex vivo results. For the ex vivo analysis, we used a custom oligonucleotide microarray containing exon probes for all known SLCs to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls. Results: There was a highly significant (p < 9.99 3 10 À7 ) overlap between the genes identified by our in silico and ex vivo strategies. The SLCs identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability. Significance: The identified SLCs are most likely to mediate pharmacoresistance in epilepsy by enhancing the intrinsic severity of epilepsy, but further functional work will be needed to fully evaluate their role. Our successful in silico strategy can be adapted in order to prioritize genes relevant to epilepsy from other gene families. Key Points• We have developed a novel in silico strategy for predicting dysregulated genes in the human epileptic focus• A novel and appealing feature of our proposed system is the ability to validate the predicted genes in silico• Using this approach, followed by ex vivo validation, we have identified the SLC genes dysregulated in the epileptic human hippocampus

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“…Earlier reports suggested the rate of mutation‐positive patients to be around 80% . More than 95% of these mutations arise de novo, and most (75%‐83%) are of paternal origin and unrelated to parental age . Several families have been reported with more than one child having DS …”

Section: Scn1a Genotype‐phenotype Correlationsmentioning

confidence: 99%

Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies

et al. 2019

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Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19-or CHD2-related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1.

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Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy

Cited by 67 publications

References 95 publications

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters

Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies

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