Three patients manifesting early infantile epileptic spasms associated with 2q24.3 microduplications

Yoshitomi, Shinsaku; Takahashi, Yukitoshi; Ishizuka, Mamiko; Yamaguchi, Tokito; Watanabe, Akito; Nasu, Hirosato; Ueda, Yuki; Ohtani, Hideyuki; Ikeda, Hiroko; Imai, Katsumi; Shigematsu, Hideo; Inoue, Yushi; Tanahashi, Yoshihiro; Aiba, Kaori; Ohta, Hodaka; Shimada, Shino; Yamamoto, Toshiyuki

doi:10.1016/j.braindev.2015.03.001

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…The most frequent were as follows: the Williams‐Beuren 7q11.23 deletion syndrome (five patients), 15q11.2 duplication syndrome, distal (three patients), 16p11.2 duplication syndrome including PRRT2 (four patients), the Potocki‐Lupski 17p11.2 duplication syndrome (two patients), and 17p13.3 deletion syndrome, also known as Miller‐Dieker lissencephaly deletion syndrome (three patients). We also identified de novo duplications at 2q24.3 and at 4p16.3‐p13, for which regions both deletions and reciprocal duplications have been associated with epilepsy …”

Section: Resultsmentioning

confidence: 87%

Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 87%

Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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“…Crucial role of SOX5 in neurodevelopment and corticogenesis is confirmed in both mice and drosophila models . SCN3A have been mostly associated with CNV, however, several patients with focal epilepsy have been reported and a single case with a highly compatible phenotype has been presented . Interestingly, upregulated expression of voltage‐gated sodium channel Na v 1.3, encoded by SCN3A , was found in cortical lesions of patients with focal dysplasia type IIb while both patients described by us (case 37 in Table S1) and Jhaveri et al had polymicrogyria.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice

et al. 2018

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Although genetic revolution of recent years has vastly expanded a list of genes implicated in epilepsies, complex architecture of epilepsy genetics is still largely unknown, consequently, universally accepted workflows for epilepsy genetic testing in a clinical practice are missing. We present a comprehensive NGS-based diagnostic approach addressing both the clinical and genetic heterogeneity of disorders involving epilepsy or seizures. A bioinformatic panel of 862 epilepsy- or seizure-associated genes was applied to Mendeliome (4813 genes) or whole-exome sequencing data as a first stage, while the second stage included untargeted variant interpretation. Eighty-six consecutive patients with epilepsy or seizures associated with neurodevelopmental disorders and/or congenital malformations were investigated. Of the 86 probands, 42 harbored pathogenic and likely pathogenic variants, giving a diagnostic yield of 49%. Two patients were diagnosed with pathogenic copy number variations and 2 had causative mitochondrial DNA variants. Eleven patients (13%) were diagnosed with diseases with specific treatments. Besides, genomic approach in diagnostics had multiple additional benefits due to mostly non-specific, overlapping, not full-blown phenotypes and abilities to diagnose novel and ultra rare epilepsy-associated diseases. Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene.

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“…In most previously published cases, patients showed different degrees of DD and in a majority also ID . However, in the maternally inherited duplication reported by Boutry‐Kryza et al, there was a family history of neonatal epilepsy affecting 10 family members .…”

Section: Discussionmentioning

confidence: 96%

“…Duplications at 2q24.3 have been described in 10 individuals presenting with early onset epilepsy during the first days of life. In two of these, the duplications were familial with several affected family members .…”

mentioning

confidence: 99%

Whole gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development

Thuresson

Buggenhout

Sheth³

et al. 2016

Clinical Genetics

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Duplications at 2q24.3 encompassing the voltage-gated sodium channel gene cluster are associated with early onset epilepsy. All cases described in the literature have presented in addition with different degrees of intellectual disability, and have involved neighbouring genes in addition to the sodium channel gene cluster. Here, we report eight new cases with overlapping duplications at 2q24 ranging from 0.05 to 7.63 Mb in size. Taken together with the previously reported cases, our study suggests that having an extra copy of SCN2A has an effect on epilepsy pathogenesis, causing benign familial infantile seizures which eventually disappear at the age of 1-2 years. However, the number of copies of SCN2A does not appear to have an effect on cognitive outcome.

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Three patients manifesting early infantile epileptic spasms associated with 2q24.3 microduplications

Cited by 7 publications

References 23 publications

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice

Whole gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development

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