Genotype-phenotype correlations in patients with de novo
            <i>KCNQ2</i>
            pathogenic variants

Malerba, Francesco; Alberini, Giulio; Balagura, Ganna; Marchese, Francesca; Amadori, Elisabetta; Riva, Antonella; Vari, Maria Stella; Gennaro, Elena Di; Madia, Francesca; Salpietro, Vincenzo; Angriman, Marco; Giordano, Lucio; Accorsi, Patrizia; Trivisano, Marina; Specchio, Nicola; Russo, Angelo; Gobbi, Giuseppe; Raviglione, Federico; Pisano, Tiziana; Marini, Carla; Mancardi, Maria Margherita; Nobili, Lino; Freri, Elena; Castellotti, Barbara; Capovilla, Giuseppe; Coppola, Antonietta; Verrotti, Alberto; Martelli, Paola; Miceli, Francesco; Maragliano, Luca; Benfenati, Fabio; Cilio, Maria Roberta; Johannesen, Katrine M; Møller, Rikke S.; Ceulemans, Berten; Minetti, Carlo; Weckhuysen, Sarah; Zara, Federico; Taglialatela, Maurizio; Striano, Pasquale

doi:10.1212/nxg.0000000000000528

Cited by 28 publications

(28 citation statements)

References 18 publications

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“…The involvement of genetic modifiers or epigenetic factors might determine the expressivity of the disease, as suggested in other genetically determined epilepsies. 32 , 33 One possible way to dissect the underlying causes of heterogeneity would be to look for common variants in other genes and/or regulatory regions in STXBP1 individuals. Another important point is the possible emergence of age-dependent differences in individuals with different variants 31 , 34 ; therefore, prospective evaluation and adult studies are crucial as they might highlight the presence of distinct natural histories in this condition.…”

Section: Discussionmentioning

confidence: 99%

Epilepsy Course and Developmental Trajectories in STXBP1 -DEE

Balagura

Xian²,

Riva³

et al. 2022

Neurol Genet

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Background and ObjectivesClinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.MethodsRetrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.ResultsForty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.DiscussionThe disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

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Section: Discussionmentioning

confidence: 99%

Epilepsy Course and Developmental Trajectories in STXBP1 -DEE

Balagura

Xian²,

Riva³

et al. 2022

Neurol Genet

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“…To investigate signaling changes that may underlie neurodevelopmental phenotypes associated with OCNDS, we focused on neuronal signaling in axonally localized ion channels, as CK2 has been shown to be highly enriched in the axon ( Bréchet et al, 2008 ) and is known to interact with axonal sodium and potassium channels ( Hien et al, 2014 ; Kang et al, 2014 ; Xu and Cooper, 2015 ). Further, these ion channels are found to be frequently mutated in both epilepsies and neurodevelopmental disorders ( Allen et al, 2020 ; Malerba et al, 2020 ), with one recent study reporting 5% of 8,565 participants carrying a mutation in axonally localized voltage gated sodium channels ( Lindy et al, 2018 ; Brunklaus and Lal, 2020 ). Of 3,000+ sites predicted be differentially phosphorylated by CK2 WT and CK2 K198R , the ten sites with the greatest differences present several interesting candidates for hypothesis generation.…”

Section: Discussionmentioning

confidence: 99%

The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

Caefer

Phan

Liddle

et al. 2022

Front. Mol. Biosci.

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Okur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by heterozygous mutations to the CSNK2A1 gene, which encodes the alpha subunit of protein kinase CK2. The most frequently occurring mutation is lysine 198 to arginine (K198R). To investigate the impact of this mutation, we first generated a high-resolution phosphorylation motif of CK2WT, including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2K198R substrate specificity was also generated. Here we report the impact of the OCNDS associated CK2K198R mutation. Contrary to prior speculation, the mutation does not result in a complete loss of function, but rather shifts the substrate specificity of the kinase. Broadly speaking the mutation leads to 1) a decreased preference for acidic residues in the +1 position, 2) a decreased preference for threonine phosphorylation, 3) an increased preference for tyrosine phosphorylation, and 4) an alteration of the tyrosine phosphorylation specificity motif. To further investigate the result of this mutation we have developed a probability-based scoring method, allowing us to predict shifts in phosphorylation in the K198R mutant relative to the wild type kinase. As an initial step we have applied the methodology to the set of axonally localized ion channels in an effort to uncover potential alterations of the phosphoproteome associated with the OCNDS disease condition.

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“…KCNQ2 variants are associated with a wide phenotypic spectrum ranging from an age-dependent, self-limiting epilepsy, to a severe DEE but also an intermediate phenotype in terms of intellectual outcomes and time to reach seizure freedom ( 38 ). In the previous study ( 39 ), the recurrent KCNQ2 variant R198Q is associated with stereotypes with refractory seizures, severely abnormal VEEG and developmental delay.…”

Section: Discussionmentioning

confidence: 99%

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

et al. 2021

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Objective: The genetic aetiology of epileptic encephalopathy (EE) is growing rapidly based on next generation sequencing (NGS) results. In this single-centre study, we aimed to investigate a cohort of Chinese children with early infantile epileptic encephalopathy (EIEE).Methods: NGS was performed on 50 children with unexplained EIEE. The clinical profiles of children with pathogenic variants were characterised and analysed in detail. Conservation analysis and homology modelling were performed to predict the impact of STXBP1 variant on the protein structure.Results: Pathogenic variants were identified in 17 (34%) of 50 children. Sixteen variants including STXBP1 (n = 2), CDKL5 (n = 2), PAFAH1B1, SCN1A (n = 9), SCN2A, and KCNQ2 were de novo, and one (PIGN) was a compound heterozygous variant. The phenotypes of the identified genes were broadened. PIGN phenotypic spectrum may include EIEE. The STXBP1 variants were predicted to affect protein stability.Significance: NGS is a useful diagnostic tool for EIEE and contributes to expanding the EIEE-associated genotypes. Early diagnosis may lead to precise therapeutic interventions and can improve the developmental outcome.

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Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants

Cited by 28 publications

References 18 publications

Epilepsy Course and Developmental Trajectories in STXBP1 -DEE

Epilepsy Course and Developmental Trajectories in STXBP1 -DEE

The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

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