A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability

Benson, Katherine; White, Máire; Allen, Nicholas M.; Byrne, Susan; Carton, Robert W.; Comerford, Elizabeth; Costello, Daniel J.; Doherty, Colin P.; Dunleavey, Brendan; El‐Naggar, Hany; Gangadharan, Nisha; Heavin, Sinéad B.; Kearney, Hugh; Lench, Nicholas J.; Lynch, John; McCormack, Mark; Regan, Mary O '; Podesta, Karl; Power, Kevin; Rogers, Anthony; Steward, Charles A.; Sweeney, Brian; Webb, David; Fitzsimons, Mary; Greally, Marie T.; Delanty, Norman; Cavalleri, Gianpiero L.

doi:10.1038/s41431-020-0610-3

Cited by 34 publications

(48 citation statements)

References 50 publications

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Section: Discussionsupporting

confidence: 87%

“…Eventually, we observed that WES was more likely to identify P/LP variants in patients with brain malformations (45%), dysmorphisms (36%) or with an epilepsy onset <1 year (36%), confirming previous studies. 5,9 In conclusion, WES represents the key strategy to reach a significant diagnostic yield, especially among adult patients with DEE whose current features may no longer allow a clinical diagnosis. Phenotype revaluation by a multidisciplinary team plays a crucial role to interpret genetic findings in each patient.…”

Section: New Genetic Findingsmentioning

confidence: 99%

“…As DEE are predominantly pediatric disorders, most of the initial implementations of NGS in a clinical setting have been addressed to newborns and children, 3‐6 while less attention has been paid to adult DEE patients who never underwent next generation genetic tests 7‐9 …”

Section: Introductionmentioning

confidence: 99%

“…newborns and children, [3][4][5][6] while less attention has been paid to adult DEE patients who never underwent next generation genetic tests. [7][8][9] This population of undiagnosed adult patients represents the socalled "lost generation," 10 who had to experience the frustration of "diagnostic odysseys" characterized by inconclusive gene-by-gene tests along decades, prior to the advent of NGS techniques.…”

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confidence: 99%

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Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

et al. 2020

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Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the longawaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them.

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Section: Discussionsupporting

confidence: 87%

Section: New Genetic Findingsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

et al. 2020

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“…Although diagnostic yield is higher in children, even among adults with intellectual disability and epilepsy of unknown cause, broad genetic testing may lead to diagnosis in over a quarter of those first tested. [3] In fact, in parallel with the patient's clinical care, DNA had been previously collected from them, with appropriate assent, as part of a long-running epilepsy genetics research programme at our centre. The 'epilepsy plus' disease category, defined as epilepsy with concomitant intellectual disability, autism spectrum disorder, structural abnormality, or unexplained cognitive decline, became available through Genomics England (GEL) in the 100,000 Genomes Project.…”

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confidence: 99%

Complex epilepsy: it’s all in the history

et al. 2020

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The patient is right-handed, in their early fifties, and carries the diagnoses of generalised tonicclonic seizures, spastic quadriparesis, severe learning disability. Generalised tonic-clonic seizures, the only reported seizure type, occur every few weeks. Current antiseizure drugs include valproate, clonazepam, levetiracetam, and lacosamide. Both the patient's condition and treatment have changed little over the past 11 years for which electronic records are available in clinic. At best, the patient mobilises with aids and communicates through simple gestures with very limited understanding. The patient attends clinic with their elderly mother and two carers. Would you try to review the syndromic diagnosis or try to establish a cause? Guidelines advocate classifying an individual's seizure and epilepsy types, the epilepsy syndrome, as well as the underlying aetiology.[1] Reviewing the diagnosis is particularly important when seizures are treatment-resistant.[2]

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The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing

et al. 2023

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Objective The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. Methods Fifty‐two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. Results Median age was 27 years (range 20‐57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). Significance Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown‐up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.

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A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability

Cited by 34 publications

References 50 publications

Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

Complex epilepsy: it’s all in the history

The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing

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