De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing

Saitsu, Hirotomo; Akita, Tenpei; Tohyama, Jun; Goldberg‐Stern, Hadassa; Kobayashi, Yu; Cohen, Roni; Kato, Mitsuhiro; Ohba, Chihiro; Miyatake, Satoko; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Fukuda, Atsuo; Matsumoto, Naomichi

doi:10.1038/srep15199

Cited by 76 publications

(120 citation statements)

References 42 publications

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“…The protein forms a functional tetramer, where each subunit is comprised of six membrane-spanning alpha helices (S1–S6), with (S1–S4) involved in voltage sensing segments and (S5–S6) forming a central pore with a voltage-dependent gating hinge that opens and closes the channel as a function of voltage. Mutations in KCNB1 have an established role in epileptic encephalopathy and previous studies (Epi4K Consortium et al 2013; Torkamani et al 2014; Saitsu et al 2015) have found six de novo causative mutations: three in the S5–S6 linker and one each in the S4, S5 and S6 helices (Figure 9a). All are predicted deleterious by SNP3D profile (Yue and Moult 2006).…”

Section: Resultsmentioning

confidence: 90%

CAGI4 SickKids clinical genomes challenge: A pipeline for identifying pathogenic variants

et al. 2017

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Compared with earlier more restricted sequencing technologies, identification of rare disease variants using whole genome sequence has the possibility of finding all causative variants, but issues of data quality and an overwhelming level of background variants complicate the analysis. The CAGI4 SickKids clinical genome challenge provided an opportunity to assess the landscape of variants found in a difficult set of 25 unsolved rare disease cases. To address the challenge, we developed a three-stage pipeline, first carefully analyzing data quality, then classifying high quality gene specific variants into seven categories, and finally examining each candidate variant for compatibility with the often complex phenotypes of these patients for final prioritization. Variants consistent with the phenotypes were found in 24 out of the 25 cases, and in a number of these, there are prioritized variants in multiple genes. Data quality analysis suggests that some of the selected variants are likely incorrect calls, complicating interpretation. The data providers followed up on three suggested variants with Sanger sequencing, and in one case a prioritized variant was confirmed as likely causative by the referring physician, providing a diagnosis in a previously intractable case.

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Section: Resultsmentioning

confidence: 90%

CAGI4 SickKids clinical genomes challenge: A pipeline for identifying pathogenic variants

et al. 2017

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“…Among them, using the 95‐genes panel, we uncovered mutations in these genes in three patients whose phenotype was concordant with previously published probands for KCNQ2 and KCNT1 , whereas the child harboring the KCNB1 mutation exhibited West syndrome. There are only seven patients reported to carry missense mutations in this gene and three of them presented infantile spasms [Torkamani et al., , Saitsu et al., ; Allen et al., ]. The patient carrying the KCNA2 variant exhibited late infantile drug‐resistant seizures followed by a good outcome with seizure‐freedom in childhood, confirming the spectrum of KCNA2 ‐related phenotypes from early and severe infantile EE to mild epilepsy with good outcome [Syrbe et al., ].…”

Section: Discussionmentioning

confidence: 87%

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

et al. 2016

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Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drugresistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions. Hum Mutat 38:216-225, 2017. C 2016 Wiley Periodicals, Inc.

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“…Developmental regression can occur in early childhood [21, 22]. In some cases, patients demonstrate behavioral abnormalities, like autistic features [23], stereotyped hand-wringing [24], hyperactivity, irritability, agitation, and aggression [25]. There are no previous reports linking KCNB1 variants to a RTT-like presentation.…”

Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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Background. Rett syndrome (RTT) is caused by mutations in methyl-CpG binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. Methods. We performed a retrospective chart review on n=319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results (3) ultimately arrived at a diagnosis other than RTT with WES. Results. n=7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These 7 patients collectively possessed pathogenic variants in 6 different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n=2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT associated features included the following: loss of hand or language skills (n=3; IQSEC2, KCNB1 × 2); disrupted sleep (n=4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n=5; FOXG1, KNCB1 × 2, MEIS2, TCF4); bruxism (n=3; KCNB1 × 2; TCF4); and hypotonia (n=7). Conclusion. Clinically-based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

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De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing

Cited by 76 publications

References 42 publications

CAGI4 SickKids clinical genomes challenge: A pipeline for identifying pathogenic variants

CAGI4 SickKids clinical genomes challenge: A pipeline for identifying pathogenic variants

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

Monogenic disorders that mimic the phenotype of Rett syndrome

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