Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation

Salinas, Valeria; Martínez, Nerina; Maturo, Josefina Pérez; Rodríguez-Quiroga, Sergio Alejandro; Zavala, Lucía; Medina, Nancy; Amartino, Hernán; Sfaello, Ignacio; Agosta, Guillermo; Serafín, Eva Maria; Morón, Dolores González; Kauffman, Marcelo; Vega, Patricia

doi:10.1016/j.ejmg.2021.104363

Cited by 13 publications

(9 citation statements)

References 31 publications

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“…In the recent decade, the development and greater availability of advanced genomic methods have led to a major shift towards etiological diagnostics of epilepsy. The number of causal genes is increasing daily, which has led to an increase in diagnostic yield [ 8 ]. The overall yield of pathogenic or likely pathogenic variants from our cohort was 23.1%.…”

Section: Discussionmentioning

confidence: 99%

“…Salinas and colleagues detected pathogenic variants initially in 38% of subjects with developmental and epileptic encephalopathies. However, after an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized and diagnosed [ 8 ]. Finally, patients were not monitored throughout the study, and we cannot access data from the diagnostic test to monitor the impact on therapeutic management.…”

Section: Discussionmentioning

confidence: 99%

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Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

Blažeković

Jerčić

Meglaj

et al. 2022

Genes

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Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based tools have shown potential in increasing diagnostic yield. The primary objective of this study was to evaluate the impact of genetic testing and to investigate the diagnostic utility of targeted gene panel sequencing. This retrospective cohort study included 277 patients aged 6 months to 17 years undergoing NGS with an epilepsy panel covering 142 genes. Of 118 variants detected, 38 (32.2%) were not described in the literature. We identified 64 pathogenic or likely pathogenic variants with an overall diagnostic yield of 23.1%. We showed a significantly higher diagnostic yield in patients with developmental delay (28.9%). Furthermore, we showed that patients with variants reported as pathogenic presented with seizures at a younger age, which led to the conclusion that such children should be included in genomic diagnostic procedures as soon as possible to achieve a correct diagnosis in a timely manner, potentially leading to better treatment and avoidance of unnecessary procedures. Describing and discovering the genetic background of the disease not only leads to a better understanding of the mechanisms of the disorder but also opens the possibility of more precise and individualized treatment based on stratified medicine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

Blažeković

Jerčić

Meglaj

et al. 2022

Genes

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“…The remaining 47 papers were published after the seminal paper in 2015 which described seven epileptic patients with SLC6A1 variants ( Carvill et al, 2015 ). Of the 47 clinically relevant papers, two were focused on attention deficit disorder ( Merriman et al, 2015 ; Yuan et al, 2017 , p1), two researched a connection with alcoholism ( Adkins et al, 2015 ; Enoch et al, 2016 ), one found SLC6A1 variants related to Alzheimer’s disease ( Zhu et al, 2020 ), one focused on connections to anxiety ( Sarris et al, 2020 ), three were focused on somatic mutations in malignant tumors ( Eshragh et al, 2017 ; Chen et al, 2020 ; Wang et al, 2022 , p1), one focused on dystonia ( Zech et al, 2017 ), one included multiple gene deletions ( Dikow et al, 2014 ; Yuan et al, 2020 ), four reported SLC6A1 variants associated with schizophrenia ( Frankle et al, 2015 ; Hoftman et al, 2015 ; Zhao et al, 2016 ; Rees et al, 2020 ), three focused on other similar mental health disorders ( Demarest et al, 2019 ; Ahring et al, 2022 ; Knight et al, 2022 ), two described genetic testing technologies ( Schijns et al, 2020 ; Salinas et al, 2021 ), and two described general developmental and epileptic encephalopathies (DEEs) without specific description of patients with SLC6A1 mutation ( Schousboe et al, 2004 ; Guillen-Guio et al, 2018 ; Galer et al, 2020 ; Salinas et al, 2021 ). Only 25 papers included clinical description of patients with neurodevelopmental symptoms and DEEs, with a likely overlap of a few patients between these papers ( Supplementary Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

A draft conceptual model of SLC6A1 neurodevelopmental disorder

Goodspeed

Mosca²,

Weitzel³

et al. 2023

Front. Neurosci.

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IntroductionSLC6A1 Neurodevelopmental Disorder (SLC6A1-NDD), first described in 2015, is a rare syndrome caused by a mutation in the SLC6A1 gene which encodes for the GABA Transporter 1 (GAT-1) protein. Epilepsy is one of the most common symptoms in patients and is often the primary treatment target, though the severity of epilepsy is variable. The impact of seizures and other symptoms of SLC6A1-NDD on patients and caregivers is wide-ranging and has not been described in a formal disease concept study.MethodsA literature search was performed using the simple search term, “SLC6A1.” Papers published before 2015, and those which did not describe the human neurodevelopmental disorder were removed from analysis. Open-ended interviews on lived experiences were conducted with two patient advocate key opinion leaders. An analysis of de-identified conversations between families of people with SLC6A1-NDD on social media was performed to quantify topics of concern.ResultsPublished literature described symptoms in all of the following domains: neurological, visual, motor, cognitive, communication, behavior, gastrointestinal, sleep, musculo-skeletal, and emotional in addition to epilepsy. Key opinion leaders noted two unpublished features: altered hand use in infants, and developmental regression with onset of epilepsy. Analysis of social media interactions confirmed that the core symptoms of epilepsy and autistic traits were prominent concerns, but also demonstrated that other symptoms have a large impact on family life.DiscussionFor rare diseases, analysis of published literature is important, but may not be as comprehensive as that which can be gleaned from spontaneous interactions between families and through qualitative interviews. This report reflects our current understanding of the lived experience of SLC6A1-NDD. The discrepancy between the domains of disease reported in the literature and those discussed in patient conversations suggests that a formal qualitative interview-based disease concept study of SLC6A1-NDD is warranted.

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“…patiënten (Halfmeyer et al, 2022;Salinas et al, 2021), bijvoorbeeld in genen die pas recent aan fenotypes gekoppeld zijn en die ten tijde van het initiële onderzoek nog geen bekende ziektegenen waren.…”

Section: Wetenschappelijk Onderzoekunclassified

Het belang van het vinden van nieuwe genetische oorzaken van epilepsie

Barakat

2023

Epilepsie

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Ondanks grote technologische vooruitgang blijft vaak de helft van de patiënten met ernstige epilepsie op de kinderleeftijd zonder een genetische diagnose. In deze bijdrage sta ik stil bij het belang van een multidisciplinaire benadering voor deze patiëntengroep en bij nieuwe genetische technologieën en analysemethoden, om alsnog een diagnose te kunnen stellen, die uiteindelijk de weg kunnen openen naar precision medicine.

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Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation

Cited by 13 publications

References 31 publications

Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

A draft conceptual model of SLC6A1 neurodevelopmental disorder

Het belang van het vinden van nieuwe genetische oorzaken van epilepsie

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