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

Brauchitsch, Sophie von; Haslinger, Denise; Lindlar, Silvia; Thiele, Holger; Bernsen, Natalie; Zahnert, Felix; Reif, Philipp S.; Balcik, Yunus; Au, Ping Yee Billie; Josephson, Colin B.; Altmüller, Janine; Strzelczyk, Adam; Knake, Susanne; Rosenow, Felix; Chiocchetti, Andreas G.; Klein, Karl Martin

doi:10.1002/epi4.12719

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…For adults presenting with epilepsy of unknown etiology, features that make monogenic epilepsy more likely include seizure onset in infancy [37], comorbid intellectual disability (ID) or developmental delay (DD) [37][38][39], and pharmacoresistant epilepsy [37]. Genetic testing in an adult cohort of patients with epilepsy revealed pathogenic variants could be missed in smaller gene panels, particularly in patients with early DD and late seizure onset [40]. In a large systematic review examining the diagnostic yield of different genetic testing modalities in all patients with epilepsy, WGS returned the highest yield (48%) compared to WES (24%), multigene panels (19%), and chromosomal microarray (9%) [41].…”

Section: Of 19mentioning

confidence: 99%

The Diagnostic Landscape of Adult Neurogenetic Disorders

Waung,

Ma,

Wheeler

et al. 2023

Biology

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Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

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Section: Of 19mentioning

confidence: 99%

The Diagnostic Landscape of Adult Neurogenetic Disorders

Waung,

Ma,

Wheeler

et al. 2023

Biology

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The role of genetic testing in adult patients with unexplained epilepsy

Chung,

Lee,

Lin

et al. 2024

Epileptic Disorders

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ObjectiveGenetic causes are often overlooked in patients with epilepsy of unknown etiology, particularly in adults. We aimed to evaluate clinical features of genetic epilepsy and the utility of genetic testing.MethodsWe retrospectively screened consecutive unrelated adult epilepsy patients at an epilepsy clinic from April 2022 to May 2023. Patients with unknown etiology or special brain lesions were classified as unexplained epilepsy. In them, patients with young‐onset seizures or family history of seizures who were recommended for and ultimately underwent genetic testing using either panel next‐generation sequencing (NGS) or whole‐exome sequencing (WES) were enrolled. A definite or probable genetic diagnosis was established through genotype–phenotype correlation. We compared the demographic characteristics between genetic epilepsy and other etiologies.ResultsOf the 374 adult epilepsy patients, 258 were classified as unexplained epilepsy, 129 were suspected of having genetic epilepsy due to young‐onset seizures or a positive family history, 33 underwent genetic testing; 13 harbored variants classified as pathogenic, and 6 reached a definite genetic diagnosis, resulting in a yield of 18%. Among the 27 patients without a definite genetic diagnosis, 7 had a nongenetic structural etiology. Patients with genetic etiology exhibited greater multisystem involvement particularly multiple structural anomalies and early childhood‐onset seizures, but wasn't directly correlated with young‐onset seizures or a positive family history. The diagnostic yield was comparable between panel NGS and WES.SignificanceIn adult patients with unexplained epilepsy, genetic epilepsy is more associated with multisystem involvement and multiple structural anomalies but not family history of seizures or young‐onset seizures.

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

Cited by 3 publications

References 36 publications

The Diagnostic Landscape of Adult Neurogenetic Disorders

The Diagnostic Landscape of Adult Neurogenetic Disorders

The role of genetic testing in adult patients with unexplained epilepsy

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

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