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1. Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions

Author

AlMail, Ali, Jamjoom, Ahmed, Pan, Amy, Feng, Min Yi, Chau, Vann, D’Gama, Alissa M., Howell, Katherine, Liang, Nicole S. Y., McTague, Amy, Poduri, Annapurna, Wiltrout, Kimberly, Bassett, Anne S., Christodoulou, John, Dupuis, Lucie, Gill, Peter, Levy, Tess, Siper, Paige, Stark, Zornitza, Vorstman, Jacob A. S., Diskin, Catherine, Jewitt, Natalie, Baribeau, Danielle, and Costain, Gregory

Published
2024
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2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, Elizabeth, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan, Chedrawi, Aziza, Hashem, Mais, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer, Sands, Tristan, Wilson, Golder, Silvertooth, Erin, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein, Ockeloen, Charlotte, Pfundt, Rolph, Kroft, Sanne, Field, Michael, Laranjeira, Francisco, Fortuna, Ana, Soares, Ana, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David, Bird, Lynne, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe, Blazo, Maria, Bijlsma, Emilia, Rosenfeld, Jill, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb, Armstrong, Ruth, and Kalscheuer, Vera

Subjects
Male, Female, Humans, Neurodevelopmental Disorders, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

3. Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders

Author

Sanchis-Juan, Alba, Megy, Karyn, Stephens, Jonathan, Armirola Ricaurte, Camila, Dewhurst, Eleanor, Low, Kayyi, French, Courtney E., Grozeva, Detelina, Stirrups, Kathleen, Erwood, Marie, McTague, Amy, Penkett, Christopher J., Shamardina, Olga, Tuna, Salih, Daugherty, Louise C., Gleadall, Nicholas, Duarte, Sofia T., Hedrera-Fernández, Antonio, Vogt, Julie, Ambegaonkar, Gautam, Chitre, Manali, Josifova, Dragana, Kurian, Manju A., Parker, Alasdair, Rankin, Julia, Reid, Evan, Wakeling, Emma, Wassmer, Evangeline, Woods, C. Geoffrey, Raymond, F. Lucy, and Carss, Keren J.

Published
2023
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5. The molecular genetic investigation of epilepsy of infancy with migrating focal seizures

Author

McTague, Amy, Kurian, M. A., Kullmann, D. M., and Scott, R. O. D.

Abstract

Epilepsy of infancy with migrating focal seizures (EIMFS) is characterised by the onset of frequent focal seizures in the first 6 months of life, a typical migratory EEG pattern and severe developmental delay. In this thesis, I report a cohort of patients with EIMFS, delineate clinical features and investigate the molecular genetic basis of this syndrome. In 2012, heterozygous mutations in the sodium-gated potassium channel KCNT1, were described in patients with EIMFS. Using a variety of genetic techniques, I have identified 12 patients with mutations in this gene. Four are novel, previously unreported mutations. Functional investigations, including protein homology modelling and electrophysiology in a xenopus oocyte model showed that all novel KCNT1 variants were gain-of-function mutations. In addition, I describe a new genetic cause of EIMFS. Within my cohort, I identified a consanguineous family with two affected children. Autozygosity mapping and whole exome sequencing revealed a novel, homozygous mutation in SLC12A5. SLC12A5 encodes KCC2, the neuronal potassium chloride co-transporter that determines the direction and polarity of GABA-mediated signalling. Through international collaboration, I found a second family with two affected children harbouring compound heterozygous SLC12A5 mutations. All three SLC12A5 variants were investigated using an overexpression HEK293 cell model. Immunoblotting and immunohistochemistry revealed decreased cell surface expression of mutant KCC2. Electrophysiology experiments showed a depolarization of the chloride reversal potential and a delayed response to chloride loading. Taken together, these results indicate that loss of KCC2 function is likely to result in abnormal neuronal inhibition in this form of EIMFS. The genetic heterogeneity in EIMFS is strong evidence that a wide variety of different pathogenic mechanisms can result in the severe epilepsy and abnormal neurodevelopment observed in this condition. Further elucidation of causative genes in both animal and cell models is needed to identify novel therapeutic targets for this devastating disorder.

Published
2018

6. The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders

Author

Genetica Klinische Genetica, Child Health, MS Radiologie, Circulatory Health, MS Neonatologie, Sidpra, Jai, Sudhakar, Sniya, Biswas, Asthik, Massey, Flavia, Turchetti, Valentina, Lau, Tracy, Cook, Edward, Alvi, Javeria Raza, Elbendary, Hasnaa M, Jewell, Jerry L, Riva, Antonella, Orsini, Alessandro, Vignoli, Aglaia, Federico, Zara, Rosenblum, Jessica, Schoonjans, An-Sofie, de Wachter, Matthias, Delgado Alvarez, Ignacio, Felipe-Rucián, Ana, Haridy, Nourelhoda A, Haider, Shahzad, Zaman, Mashaya, Banu, Selina, Anwaar, Najwa, Rahman, Fatima, Maqbool, Shazia, Yadav, Rashmi, Salpietro, Vincenzo, Maroofian, Reza, Patel, Rajan, Radhakrishnan, Rupa, Prabhu, Sanjay P, Lichtenbelt, Klaske, Stewart, Helen, Murakami, Yoshiko, Löbel, Ulrike, D'Arco, Felice, Wakeling, Emma, Jones, Wendy, Hay, Eleanor, Bhate, Sanjay, Jacques, Thomas S, Mirsky, David M, Whitehead, Matthew T, Zaki, Maha S, Sultan, Tipu, Striano, Pasquale, Jansen, Anna C, Lequin, Maarten, de Vries, Linda S, Severino, Mariasavina, Edmondson, Andrew C, Menzies, Lara, Campeau, Philippe M, Houlden, Henry, McTague, Amy, Efthymiou, Stephanie, Mankad, Kshitij, Genetica Klinische Genetica, Child Health, MS Radiologie, Circulatory Health, MS Neonatologie, Sidpra, Jai, Sudhakar, Sniya, Biswas, Asthik, Massey, Flavia, Turchetti, Valentina, Lau, Tracy, Cook, Edward, Alvi, Javeria Raza, Elbendary, Hasnaa M, Jewell, Jerry L, Riva, Antonella, Orsini, Alessandro, Vignoli, Aglaia, Federico, Zara, Rosenblum, Jessica, Schoonjans, An-Sofie, de Wachter, Matthias, Delgado Alvarez, Ignacio, Felipe-Rucián, Ana, Haridy, Nourelhoda A, Haider, Shahzad, Zaman, Mashaya, Banu, Selina, Anwaar, Najwa, Rahman, Fatima, Maqbool, Shazia, Yadav, Rashmi, Salpietro, Vincenzo, Maroofian, Reza, Patel, Rajan, Radhakrishnan, Rupa, Prabhu, Sanjay P, Lichtenbelt, Klaske, Stewart, Helen, Murakami, Yoshiko, Löbel, Ulrike, D'Arco, Felice, Wakeling, Emma, Jones, Wendy, Hay, Eleanor, Bhate, Sanjay, Jacques, Thomas S, Mirsky, David M, Whitehead, Matthew T, Zaki, Maha S, Sultan, Tipu, Striano, Pasquale, Jansen, Anna C, Lequin, Maarten, de Vries, Linda S, Severino, Mariasavina, Edmondson, Andrew C, Menzies, Lara, Campeau, Philippe M, Houlden, Henry, McTague, Amy, Efthymiou, Stephanie, and Mankad, Kshitij

Published
2024

7. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author

Lenaerts, Lisa, Reynhout, Sara, Verbinnen, Iris, Laumonnier, Frédéric, Toutain, Annick, Bonnet-Brilhault, Frédérique, Hoorne, Yana, Joss, Shelagh, Chassevent, Anna K., Smith-Hicks, Constance, Loeys, Bart, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mehta, Sarju G., Chung, Wendy K., Devriendt, Koenraad, Holder, Susan E., Jewett, Tamison, Baldwin, Lauren M., Wilson, William G., Towner, Shelley, Srivastava, Siddharth, Johnson, Hannah F., Daumer-Haas, Cornelia, Baethmann, Martina, Ruiz, Anna, Gabau, Elisabeth, Jain, Vani, Varghese, Vinod, Al-Beshri, Ali, Fulton, Stephen, Wechsberg, Oded, Orenstein, Naama, Prescott, Katrina, Childs, Anne-Marie, Faivre, Laurence, Moutton, Sébastien, Sullivan, Jennifer A., Shashi, Vandana, Koudijs, Suzanne M., Heijligers, Malou, Kivuva, Emma, McTague, Amy, Male, Alison, van Ierland, Yvette, Plecko, Barbara, Maystadt, Isabelle, Hamid, Rizwan, Hannig, Vickie L., Houge, Gunnar, and Janssens, Veerle

Published
2021
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8. SLC25A22 is a novel gene for migrating partial seizures in infancy

Author

Poduri, Annapurna, Heinzen, Erin L, Chitsazzadeh, Vida, Lasorsa, Francesco Massimo, Elhosary, P Christina, LaCoursiere, Christopher M, Martin, Emilie, Yuskaitis, Christopher J, Hill, Robert Sean, Atabay, Kutay Deniz, Barry, Brenda, Partlow, Jennifer N, Bashiri, Fahad A, Zeidan, Radwan M, Elmalik, Salah A, Kabiraj, Mohammad MU, Kothare, Sanjeev, Stödberg, Tommy, McTague, Amy, Kurian, Manju A, Scheffer, Ingrid E, Barkovich, A James, Palmieri, Ferdinando, Salih, Mustafa A, and Walsh, Christopher A

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Neurodegenerative, Human Genome, Biotechnology, Brain Disorders, Epilepsy, Clinical Research, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Consanguinity, Epilepsy, Benign Neonatal, Exome, Female, Genetic Linkage, Humans, Infant, Newborn, Male, Mitochondrial Membrane Transport Proteins, Pedigree, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify a genetic cause for migrating partial seizures in infancy (MPSI).MethodsWe characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.ResultsIn a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport.InterpretationWe have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22.

Published
2013

9. Pediatric epilepsy surgery from 2000 to 2018: Changes in referral and surgical volumes, patient characteristics, genetic testing, and postsurgical outcomes

Author

Eriksson, Maria H., primary, Whitaker, Kirstie J., additional, Booth, John, additional, Piper, Rory J., additional, Chari, Aswin, additional, Martin Sanfilippo, Patricia, additional, Caballero, Ana Perez, additional, Menzies, Lara, additional, McTague, Amy, additional, Adler, Sophie, additional, Wagstyl, Konrad, additional, Tisdall, Martin M., additional, Cross, J. Helen, additional, and Baldeweg, Torsten, additional

Published
2023
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10. Predicting seizure outcome after epilepsy surgery: Do we need more complex models, larger samples, or better data?

Author

Eriksson, Maria H., primary, Ripart, Mathilde, additional, Piper, Rory J., additional, Moeller, Friederike, additional, Das, Krishna B., additional, Eltze, Christin, additional, Cooray, Gerald, additional, Booth, John, additional, Whitaker, Kirstie J., additional, Chari, Aswin, additional, Martin Sanfilippo, Patricia, additional, Perez Caballero, Ana, additional, Menzies, Lara, additional, McTague, Amy, additional, Tisdall, Martin M., additional, Cross, J. Helen, additional, Baldeweg, Torsten, additional, Adler, Sophie, additional, and Wagstyl, Konrad, additional

Published
2023
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11. P305: Evaluation of the feasibility, diagnostic yield, and utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): An international pilot study

Author

Yan Liang, Nicole Si, Costain, Gregory, D'Gama, Alissa, McTague, Amy, Howell, Katherine, Chau, Vann, Mulhern, Sarah, Poduri, Annapurna, Scheffer, Ingrid, Sheidley, Beth, Curtis, Meredith, Higginbotham, Edward, Khan, Tayyaba, McRae, Lyndsey, Wiltrout, Kimberly, Hayeems, Robin, Jain, Puneet, Lunke, Sebastian, Marshall, Christian, Chitty, Lyn, Rockowitz, Shira, Stark, Zornitza, and White, Susan

Published
2024
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12. P249: Gaps in the phenotype descriptions of ultra-rare genetic conditions: Review and multi-center consensus reporting guidelines

Author

AlMail, Ali, Jamjoom, Ahmed, Pan, Amy, Feng, Anna, Chau, Vann, D'Gama, Alissa, Howell, Katherine, Yan Liang, Nicole Si, McTague, Amy, Poduri, Annapurna, Wiltrout, Kimberly, Bassett, Anne, Christodoulou, John, Dupuis, Lucie, Gill, Peter, Levy, Tess, Siper, Paige, Stark, Zornitza, Vorstman, Jacob, Diskin, Catherine, Jewitt, Natalie, Baribeau, Danielle, and Costain, Gregory

Published
2024
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13. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogne, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stephanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Benedicte, Warde, Marie-Therese Abi, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Polsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zoe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikael, Mohammad, Shekeeb S., Armstrong, Ruth, Kalscheuer, Vera M., Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogne, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stephanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Benedicte, Warde, Marie-Therese Abi, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Polsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zoe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikael, Mohammad, Shekeeb S., Armstrong, Ruth, and Kalscheuer, Vera M.

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., Funding Agencies|Fondazione AIRC per la Ricerca sul Cancro [IG 21558]; Italian Ministry for University and Research (MIUR) [PRIN 20174TB8KW]; FWO [1861419N]; Queen Elisabeth Medical Foundation; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]; CPA grant [PG01217]; NHMRC Principal Research Fellowship [GNT1120615]; BICARE, Australia; King Salman Center for Disability Research [RG-2022-010, RG-2022-011]; MRC [MR/T007087/1]; GOSH Charity [VS0122]; Rosetrees Trust [CF2\100018]; NHMRC Investigator Grant [GNT20081]; Projekt DEAL; NIHR GOSH BRC

Published
2023
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14. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications

Author

Brunklaus, Andreas, Brünger, Tobias, Feng, Tony, Fons, Carmen, Lehikoinen, Anni, Panagiotakaki, Eleni, Vintan, Mihaela-Adela, Symonds, Joseph, Andrew, James, Arzimanoglou, Alexis, Gallois, Julie, Delima, Sarah, Hanrahan, Donncha, Lesca, Gaetan, MacLeod, Stewart, Marjanovic, Dragan, McTague, Amy, Nuñez-Enamorado, Noemi, Perez-Palma, Eduardo, Perry, M. Scott, Pysden, Karen, Russ-Hall, Sophie J., Scheffer, Ingrid E., Sully, Krystal, Syrbe, Steffen, Vaher, Ulvi, Velayutham, Murugan, Vogt, Julie, Weiss, Shelly, Wirrell, Elaine, Zuberi, Sameer M., Lal, Dennis, Møller, Rikke S., and Mantegazza, Massimo

Abstract

No abstract available.

Published
2022

16. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, Kalscheuer, Vera M, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, and Kalscheuer, Vera M

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2022

17. Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Author

Johannesen, Katrine M., Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A., Perez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A., Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H., Verbeek, Nienke E., van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M. H., Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R., Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K., Dinopoulos, Argirios, Campbell, Arthur J., Lal, Dennis, Lederer, Damien, Liao, Vivian W. Y., Ahring, Philip K., Moller, Rikke S., Gardella, Elena, Johannesen, Katrine M., Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A., Perez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A., Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H., Verbeek, Nienke E., van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M. H., Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R., Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K., Dinopoulos, Argirios, Campbell, Arthur J., Lal, Dennis, Lederer, Damien, Liao, Vivian W. Y., Ahring, Philip K., Moller, Rikke S., and Gardella, Elena

Abstract

Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Published
2022

18. Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Author

Genetica Klinische Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Child Health, Johannesen, Katrine M, Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A, Pérez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A, Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H, Verbeek, Nienke E, van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M H, Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R, Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K, Dinopoulos, Argirios, Campbell, Arthur J, Lal, Dennis, Lederer, Damien, Liao, Vivian W Y, Ahring, Philip K, Møller, Rikke S, Gardella, Elena, Genetica Klinische Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Child Health, Johannesen, Katrine M, Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A, Pérez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A, Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H, Verbeek, Nienke E, van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M H, Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R, Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K, Dinopoulos, Argirios, Campbell, Arthur J, Lal, Dennis, Lederer, Damien, Liao, Vivian W Y, Ahring, Philip K, Møller, Rikke S, and Gardella, Elena

Published
2022

19. Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

Author

Johannesen, Katrine M., primary, Iqbal, Sumaiya, additional, Guazzi, Milena, additional, Mohammadi, Nazanin A., additional, Pérez-Palma, Eduardo, additional, Schaefer, Elise, additional, De Saint Martin, Anne, additional, Abiwarde, Marie Therese, additional, McTague, Amy, additional, Pons, Roser, additional, Piton, Amelie, additional, Kurian, Manju A., additional, Ambegaonkar, Gautam, additional, Firth, Helen, additional, Sanchis-Juan, Alba, additional, Deprez, Marie, additional, Jansen, Katrien, additional, De Waele, Liesbeth, additional, Briltra, Eva H., additional, Verbeek, Nienke E., additional, van Kempen, Marjan, additional, Fazeli, Walid, additional, Striano, Pasquale, additional, Zara, Federico, additional, Visser, Gerhard, additional, Braakman, Hilde M.H., additional, Haeusler, Martin, additional, Elbracht, Miriam, additional, Vaher, Ulvi, additional, Smol, Thomas, additional, Lemke, Johannes R., additional, Platzer, Konrad, additional, Kennedy, Joanna, additional, Klein, Karl Martin, additional, Au, Ping Yee Billie, additional, Smyth, Kimberly, additional, Kaplan, Julie, additional, Thomas, Morgan, additional, Dewenter, Malin K., additional, Dinopoulos, Argirios, additional, Campbell, Arthur J., additional, Lal, Dennis, additional, Lederer, Damien, additional, Liao, Vivian W.Y., additional, Ahring, Philip K., additional, Møller, Rikke S., additional, and Gardella, Elena, additional

Published
2022
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23. The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy

Author

Genetica Klinische Genetica, Datta, Alexandre N, Bahi-Buisson, Nadia, Bienvenu, Thierry, Buerki, Sarah E, Gardiner, Fiona, Cross, J Helen, Heron, Bénédicte, Kaminska, Anna, Korff, Christian M, Lepine, Anne, Lesca, Gaetan, McTague, Amy, Mefford, Heather C, Mignot, Cyrill, Milh, Matthieu, Piton, Amélie, Pressler, Ronit M, Ruf, Susanne, Sadleir, Lynette G, de Saint Martin, Anne, Van Gassen, Koen, Verbeek, Nienke E, Ville, Dorothée, Villeneuve, Nathalie, Zacher, Pia, Scheffer, Ingrid E, Lemke, Johannes R, Genetica Klinische Genetica, Datta, Alexandre N, Bahi-Buisson, Nadia, Bienvenu, Thierry, Buerki, Sarah E, Gardiner, Fiona, Cross, J Helen, Heron, Bénédicte, Kaminska, Anna, Korff, Christian M, Lepine, Anne, Lesca, Gaetan, McTague, Amy, Mefford, Heather C, Mignot, Cyrill, Milh, Matthieu, Piton, Amélie, Pressler, Ronit M, Ruf, Susanne, Sadleir, Lynette G, de Saint Martin, Anne, Van Gassen, Koen, Verbeek, Nienke E, Ville, Dorothée, Villeneuve, Nathalie, Zacher, Pia, Scheffer, Ingrid E, and Lemke, Johannes R

Published
2021

25. Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, primary, Sticht, Heinrich, additional, Zacher, Pia, additional, Popp, Bernt, additional, Babcock, Holly E., additional, Bakker, Dewi P., additional, Barwick, Katy, additional, Bonfert, Michaela V., additional, Bönnemann, Carsten G., additional, Brilstra, Eva H., additional, Chung, Wendy K., additional, Clarke, Angus J., additional, Devine, Patrick, additional, Donkervoort, Sandra, additional, Fraser, Jamie L., additional, Friedman, Jennifer, additional, Gates, Alyssa, additional, Ghoumid, Jamal, additional, Hobson, Emma, additional, Horvath, Gabriella, additional, Keller-Ramey, Jennifer, additional, Keren, Boris, additional, Kurian, Manju A., additional, Lee, Virgina, additional, Leppig, Kathleen A., additional, Lundgren, Johan, additional, McDonald, Marie T., additional, McLaughlin, Heather M., additional, McTague, Amy, additional, Mefford, Heather C., additional, Mignot, Cyril, additional, Mikati, Mohamad A., additional, Nava, Caroline, additional, Raymond, F. Lucy, additional, Sampson, Julian R., additional, Sanchis-Juan, Alba, additional, Shashi, Vandana, additional, Shieh, Joseph T.C., additional, Shinawi, Marwan, additional, Slavotinek, Anne, additional, Stödberg, Tommy, additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Taylor, Ashley C., additional, Toler, Tomi L., additional, van den Boogaard, Marie-José, additional, van der Crabben, Saskia N., additional, van Gassen, Koen L.I., additional, van Jaarsveld, Richard H., additional, Van Ziffle, Jessica, additional, Wadley, Alexandrea F., additional, Wagner, Matias, additional, Wigby, Kristen, additional, Wortmann, Saskia B., additional, Zarate, Yuri A., additional, Møller, Rikke S., additional, Lemke, Johannes R., additional, and Platzer, Konrad, additional

Published
2021
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26. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, primary, Sticht, Heinrich, additional, Zacher, Pia, additional, Popp, Bernt, additional, Babcock, Holly E., additional, Bakker, Dewi P., additional, Barwick, Katy, additional, Bonfert, Michaela V., additional, Bönnemann, Carsten G., additional, Brilstra, Eva H., additional, Chung, Wendy K., additional, Clarke, Angus J., additional, Devine, Patrick, additional, Donkervoort, Sandra, additional, Fraser, Jamie L., additional, Friedman, Jennifer, additional, Gates, Alyssa, additional, Ghoumid, Jamal, additional, Hobson, Emma, additional, Horvath, Gabriella, additional, Keller-Ramey, Jennifer, additional, Keren, Boris, additional, Kurian, Manju A., additional, Lee, Virgina, additional, Leppig, Kathleen A., additional, Lundgren, Johan, additional, McDonald, Marie T., additional, McLaughlin, Heather M., additional, McTague, Amy, additional, Mefford, Heather C., additional, Mignot, Cyril, additional, Mikati, Mohamad A., additional, Nava, Caroline, additional, Raymond, F. Lucy, additional, Sampson, Julian R., additional, Sanchis-Juan, Alba, additional, Shashi, Vandana, additional, Shieh, Joseph T.C., additional, Shinawi, Marwan, additional, Slavotinek, Anne, additional, Stödberg, Tommy, additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Taylor, Ashley C., additional, Toler, Tomi L., additional, van den Boogaard, Marie-José, additional, van der Crabben, Saskia N., additional, van Gassen, Koen L.I., additional, van Jaarsveld, Richard H., additional, Van Ziffle, Jessica, additional, Wadley, Alexandrea F., additional, Wagner, Matias, additional, Wigby, Kristen, additional, Wortmann, Saskia B., additional, Zarate, Yuri A., additional, Møller, Rikke S., additional, Lemke, Johannes R., additional, and Platzer, Konrad, additional

Published
2021
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27. Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

Author

Myers, Kenneth A., primary, Marini, Carla, additional, Carvill, Gemma L., additional, McTague, Amy, additional, Panetta, Julie, additional, Stutterd, Chloe, additional, Stanley, Thorsten, additional, Marin, Samantha, additional, Nguyen, John, additional, Barba, Carmen, additional, Rosati, Anna, additional, Scott, Richard H., additional, Mefford, Heather C., additional, Guerrini, Renzo, additional, and Scheffer, Ingrid E., additional

Published
2021
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29. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy

Author

McTague, Amy, Nair, Umesh, Malhotra, Sony, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngoh, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William, Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. 'Kling', Cross, J. Helen, Topf, Maya, Petrou, Steven, and Kurian, Manju A.

Subjects
Models, Molecular, Potassium Channels, Xenopus, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Article, Membrane Potentials, Structure-Activity Relationship, Potassium Channel Blockers, Animals, Humans, Computer Simulation, Genetic Predisposition to Disease, Age of Onset, Models, Genetic, Infant, Newborn, Infant, Quinidine, Phenotype, Child, Preschool, Mutation, Oocytes, Anticonvulsants, Epilepsies, Partial
Abstract

Objective To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. Methods We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. Results We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. Conclusions Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

Published
2018

30. The phenotypic spectrum of X‐linked, infantile onset ALG13‐related developmental and epileptic encephalopathy

Author

Datta, Alexandre N., primary, Bahi‐Buisson, Nadia, additional, Bienvenu, Thierry, additional, Buerki, Sarah E., additional, Gardiner, Fiona, additional, Cross, J. Helen, additional, Heron, Bénédicte, additional, Kaminska, Anna, additional, Korff, Christian M., additional, Lepine, Anne, additional, Lesca, Gaetan, additional, McTague, Amy, additional, Mefford, Heather C., additional, Mignot, Cyrill, additional, Milh, Matthieu, additional, Piton, Amélie, additional, Pressler, Ronit M., additional, Ruf, Susanne, additional, Sadleir, Lynette G., additional, de Saint Martin, Anne, additional, Van Gassen, Koen, additional, Verbeek, Nienke E., additional, Ville, Dorothée, additional, Villeneuve, Nathalie, additional, Zacher, Pia, additional, Scheffer, Ingrid E., additional, and Lemke, Johannes R., additional

Published
2021
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31. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum

Author

McTague, Amy, Appleton, Richard, Avula, Shivaram, Cross, J. Helen, King, Mary D., Jacques, Thomas S., Bhate, Sanjay, Cronin, Anthony, Curran, Andrew, Desurkar, Archana, Farrell, Michael A., Hughes, Elaine, Jefferson, Rosalind, Lascelles, Karine, Livingston, John, Meyer, Esther, McLellan, Ailsa, Poduri, Annapurna, Scheffer, Ingrid E., Spinty, Stefan, Kurian, Manju A., and Kneen, Rachel

Published
2013
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32. Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

Author

Absalom, Nathan L, primary, Liao, Vivian W Y, additional, Kothur, Kavitha, additional, Indurthi, Dinesh C, additional, Bennetts, Bruce, additional, Troedson, Christopher, additional, Mohammad, Shekeeb S, additional, Gupta, Sachin, additional, McGregor, Iain S, additional, Bowen, Michael T, additional, Lederer, Damien, additional, Mary, Sandrine, additional, De Waele, Liesbeth, additional, Jansen, Katrien, additional, Gill, Deepak, additional, Kurian, Manju A, additional, McTague, Amy, additional, Møller, Rikke S, additional, Ahring, Philip K, additional, Dale, Russell C, additional, and Chebib, Mary, additional

Published
2020
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33. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Gorman, Kathleen M, Meyer, Esther, Grozeva, Detelina, Spinelli, Egidio, McTague, Amy, Sanchis-Juan, Alba, Carss, Keren J, Bryant, Emily, Reich, Adi, Schneider, Amy L, Pressler, Ronit M, Simpson, Michael A, Debelle, Geoff D, Wassmer, Evangeline, Morton, Jenny, Sieciechowicz, Diana, Jan-Kamsteeg, Eric, Paciorkowski, Alex R, King, Mary D, Cross, J Helen, Poduri, Annapurna, Mefford, Heather C, Scheffer, Ingrid E, Haack, Tobias B, McCullagh, Gary, Deciphering Developmental Disorders Study, UK10K Consortium, NIHR BioResource, Millichap, John J, Carvill, Gemma L, Clayton-Smith, Jill, Maher, Eamonn R, Raymond, F Lucy, Kurian, Manju A, Maher, Eamonn [0000-0002-6226-6918], and Apollo - University of Cambridge Repository

Subjects
CACNA1B, epilepsy, epilepsy-dyskinesia, health care economics and organizations, developmental and epileptic encephalopathy (DEE)
Abstract

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2019

34. Structural mapping of GABRB3variants reveals genotype–phenotype correlations

Author

Johannesen, Katrine M., Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A., Pérez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A., Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H., Verbeek, Nienke E., van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M.H., Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R., Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K., Dinopoulos, Argirios, Campbell, Arthur J., Lal, Dennis, Lederer, Damien, Liao, Vivian W.Y., Ahring, Philip K., Møller, Rikke S., and Gardella, Elena

Abstract

Pathogenic variants in GABRB3have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations.

Published
2022
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36. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Gorman, Kathleen M., primary, Meyer, Esther, additional, Grozeva, Detelina, additional, Spinelli, Egidio, additional, McTague, Amy, additional, Sanchis-Juan, Alba, additional, Carss, Keren J., additional, Bryant, Emily, additional, Reich, Adi, additional, Schneider, Amy L., additional, Pressler, Ronit M., additional, Simpson, Michael A., additional, Debelle, Geoff D., additional, Wassmer, Evangeline, additional, Morton, Jenny, additional, Sieciechowicz, Diana, additional, Jan-Kamsteeg, Eric, additional, Paciorkowski, Alex R., additional, King, Mary D., additional, Cross, J. Helen, additional, Poduri, Annapurna, additional, Mefford, Heather C., additional, Scheffer, Ingrid E., additional, Haack, Tobias B., additional, McCullagh, Gary, additional, Millichap, John J., additional, Carvill, Gemma L., additional, Clayton-Smith, Jill, additional, Maher, Eamonn R., additional, Raymond, F. Lucy, additional, Kurian, Manju A., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V. K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J., additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I. Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, Hurles, Matthew E., additional, Al Turki, Saeed, additional, Anderson, Carl, additional, Anney, Richard, additional, Antony, Dinu, additional, Artigas, Maria Soler, additional, Ayub, Muhammad, additional, Balasubramaniam, Senduran, additional, Barroso, Inês, additional, Beales, Phil, additional, Bentham, Jamie, additional, Bhattacharya, Shoumo, additional, Birney, Ewan, additional, Blackwood, Douglas, additional, Bobrow, Martin, additional, Bochukova, Elena, additional, Bolton, Patrick, additional, Bounds, Rebecca, additional, Boustred, Chris, additional, Breen, Gerome, additional, Calissano, Mattia, additional, Carss, Keren, additional, Chatterjee, Krishna, additional, Chen, Lu, additional, Ciampi, Antonio, additional, Cirak, Sebhattin, additional, Clapham, Peter, additional, Clement, Gail, additional, Coates, Guy, additional, Collier, David, additional, Cosgrove, Catherine, additional, Cox, Tony, additional, Craddock, Nick, additional, Crooks, Lucy, additional, Curran, Sarah, additional, Curtis, David, additional, Daly, Allan, additional, Day-Williams, Aaron, additional, Day, Ian N.M., additional, Down, Thomas, additional, Du, Yuanping, additional, Dunham, Ian, additional, Edkins, Sarah, additional, Ellis, Peter, additional, Evans, David, additional, Faroogi, Sadaf, additional, Fatemifar, Ghazaleh, additional, Fitzpatrick, David R., additional, Flicek, Paul, additional, Flyod, James, additional, Foley, A. Reghan, additional, Franklin, Christopher S., additional, Futema, Marta, additional, Gallagher, Louise, additional, Geihs, Matthias, additional, Geschwind, Daniel, additional, Griffin, Heather, additional, Guo, Xueqin, additional, Guo, Xiaosen, additional, Gurling, Hugh, additional, Hart, Deborah, additional, Hendricks, Audrey, additional, Holmans, Peter, additional, Howie, Bryan, additional, Huang, Liren, additional, Hubbard, Tim, additional, Humphries, Steve E., additional, Hysi, Pirro, additional, Jackson, David K., additional, Jamshidi, Yalda, additional, Jing, Tian, additional, Joyce, Chris, additional, Kaye, Jane, additional, Keane, Thomas, additional, Keogh, Julia, additional, Kemp, John, additional, Kennedy, Karen, additional, Kolb-Kokocinski, Anja, additional, Lachance, Genevieve, additional, Langford, Cordelia, additional, Lawson, Daniel, additional, Lee, Irene, additional, Lek, Monkol, additional, Liang, Jieqin, additional, Lin, Hong, additional, Li, Rui, additional, Li, Yingrui, additional, Liu, Ryan, additional, Lönnqvist, Jouko, additional, Lopes, Margarida, additional, Iotchkova, Valentina, additional, MacArthur, Daniel, additional, Marchini, Jonathan, additional, Maslen, John, additional, Massimo, Mangino, additional, Mathieson, Iain, additional, Marenne, Gaëlle, additional, McGuffin, Peter, additional, McIntosh, Andrew, additional, McKechanie, Andrew G., additional, McQuillin, Andrew, additional, Metrustry, Sarah, additional, Mitchison, Hannah, additional, Moayyeri, Alireza, additional, Morris, James, additional, Muntoni, Francesco, additional, Northstone, Kate, additional, O'Donnovan, Michael, additional, Onoufriadis, Alexandros, additional, O'Rahilly, Stephen, additional, Oualkacha, Karim, additional, Owen, Michael J., additional, Palotie, Aarno, additional, Panoutsopoulou, Kalliope, additional, Parker, Victoria, additional, Parr, Jeremy R., additional, Paternoster, Lavinia, additional, Paunio, Tiina, additional, Payne, Felicity, additional, Pietilainen, Olli, additional, Plagnol, Vincent, additional, Quaye, Lydia, additional, Quail, Michael A., additional, Rehnström, Karola, additional, Ring, Susan, additional, Ritchie, Graham R.S., additional, Roberts, Nicola, additional, Savage, David B., additional, Scambler, Peter, additional, Schiffels, Stephen, additional, Schmidts, Miriam, additional, Schoenmakers, Nadia, additional, Semple, Robert K., additional, Serra, Eva, additional, Sharp, Sally I., additional, Shin, So-Youn, additional, Skuse, David, additional, Small, Kerrin, additional, Southam, Lorraine, additional, Spasic-Boskovic, Olivera, additional, St Clair, David, additional, Stalker, Jim, additional, Stevens, Elizabeth, additional, St Pourcian, Beate, additional, Sun, Jianping, additional, Suvisaari, Jaana, additional, Tachmazidou, Ionna, additional, Tobin, Martin D., additional, Valdes, Ana, additional, Van Kogelenberg, Margriet, additional, Visscher, Peter M., additional, Wain, Louise V., additional, Walters, James T.R., additional, Wang, Guangbiao, additional, Wang, Jun, additional, Wang, Yu, additional, Ward, Kirsten, additional, Wheeler, Elanor, additional, Whyte, Tamieka, additional, Williams, Hywel, additional, Williamson, Kathleen A., additional, Wilson, Crispian, additional, Wong, Kim, additional, Xu, ChangJiang, additional, Yang, Jian, additional, Zhang, Fend, additional, Zhang, Pingbo, additional, Aitman, Timothy, additional, Alachkar, Hana, additional, Ali, Sonia, additional, Allen, Louise, additional, Allsup, David, additional, Ambegaonkar, Gautum, additional, Anderson, Julie, additional, Antrobus, Richard, additional, Arno, Gavin, additional, Arumugakani, Gururaj, additional, Ashford, Sofie, additional, Astle, William, additional, Attwood, Antony, additional, Austin, Steve, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Bariana, Tadbir K., additional, Baxendale, Helen, additional, Bennett, David, additional, Bethune, Claire, additional, Bibi, Shahnaz, additional, Bleda, Marta, additional, Boggard, Harm, additional, Bolton-Maggs, Paula, additional, Booth, Claire, additional, Bradley, John R., additional, Brady, Angie, additional, Brown, Matthew, additional, Browning, Michael, additional, Bryson, Christine, additional, Burns, Siobhan, additional, Calleja, Paul, additional, Carmichael, Jenny, additional, Caulfield, Mark, additional, Chalmers, Elizabeth, additional, Chandra, Anita, additional, Chinnery, Patrick, additional, Chitre, Manali, additional, Church, Colin, additional, Clement, Emma, additional, Clements-Brod, Naomi, additional, Coghlan, Gerry, additional, Collins, Peter, additional, Cooper, Nichola, additional, Creaser-Myers, Amanda, additional, DaCosta, Rosa, additional, Daugherty, Louise, additional, Davies, Sophie, additional, Davis, John, additional, De Vries, Minka, additional, Deegan, Patrick, additional, Deevi, Sri V.V., additional, Devlin, Lisa, additional, Dewhurst, Eleanor, additional, Doffinger, Rainer, additional, Dormand, Natalie, additional, Drewe, Elizabeth, additional, Edgar, David, additional, Egner, William, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Everington, Tamara, additional, Favier, Remi, additional, Firth, Helen, additional, Fletcher, Debra, additional, Fox, James C., additional, Frary, Amy, additional, Freson, Kathleen, additional, Furie, Bruce, additional, Furnell, Abigail, additional, Gale, Daniel, additional, Gardham, Alice, additional, Gattens, Michael, additional, Ghataorhe, Pavandeep K., additional, Ghurye, Rohit, additional, Gibbs, Simon, additional, Gilmour, Kimberley, additional, Gissen, Paul, additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavel, additional, Gräf, Stefan, additional, Greene, Daniel, additional, Greenhalgh, Alan, additional, Greinacher, Andreas, additional, Grigoriadou, Sofia, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Haimel, Matthias, additional, Halmagyi, Csaba, additional, Hammerton, Tracey, additional, Hart, Daniel, additional, Hayman, Grant, additional, Heemskerk, Johan W.M., additional, Henderson, Robert, additional, Hensiek, Anke, additional, Henskens, Yvonne, additional, Herwadkar, Archana, additional, Hu, Fengyuan, additional, Huissoon, Aarnoud, additional, Humbert, Marc, additional, James, Roger, additional, Jolles, Stephen, additional, Kazmi, Rashid, additional, Keeling, David, additional, Kelleher, Peter, additional, Kelly, Anne M., additional, Kennedy, Fiona, additional, Kiely, David, additional, Kingston, Nathalie, additional, Koziell, Ania, additional, Krishnakumar, Deepa, additional, Kuijpers, Taco W., additional, Kumararatne, Dinakantha, additional, Kurian, Manju, additional, Laffan, Michael A., additional, Lambert, Michele P., additional, Allen, Hana Lango, additional, Lawrie, Allan, additional, Lear, Sara, additional, Lentaigne, Claire, additional, Liesner, Ri, additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena, additional, Machado, Rajiv, additional, Mackenzie, Rob, additional, MacLaren, Robert, additional, Maher, Eamonn, additional, Maimaris, Jesmeen, additional, Mangles, Sarah, additional, Manson, Ania, additional, Mapeta, Rutendo, additional, Markus, Hugh S., additional, Martin, Jennifer, additional, Masati, Larahmie, additional, Mathias, Mary, additional, Matser, Vera, additional, Maw, Anna, additional, McDermott, Elizabeth, additional, McJannet, Coleen, additional, Meacham, Stuart, additional, Meehan, Sharon, additional, Megy, Karyn, additional, Michaelides, Michel, additional, Millar, Carolyn M., additional, Moledina, Shahin, additional, Moore, Anthony, additional, Morrell, Nicholas, additional, Mumford, Andrew, additional, Murng, Sai, additional, Murphy, Elaine, additional, Nejentsev, Sergey, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, Oksenhendler, Eric, additional, Ouwehand, Willem H., additional, Papadia, Sofia, additional, Parker, Alasdair, additional, Pasi, John, additional, Patch, Chris, additional, Payne, Jeanette, additional, Peacock, Andrew, additional, Peerlinck, Kathelijne, additional, Penkett, Christopher J., additional, Pepke-Zaba, Joanna, additional, Perry, David J., additional, Pollock, Val, additional, Polwarth, Gary, additional, Ponsford, Mark, additional, Qasim, Waseem, additional, Quinti, Isabella, additional, Rankin, Stuart, additional, Rehnstrom, Karola, additional, Reid, Evan, additional, Rhodes, Christopher J., additional, Richards, Michael, additional, Richardson, Sylvia, additional, Richter, Alex, additional, Roberts, Irene, additional, Rondina, Matthew, additional, Roughley, Catherine, additional, Rue-Albrecht, Kevin, additional, Samarghitean, Crina, additional, Santra, Saikat, additional, Sargur, Ravishankar, additional, Savic, Sinisa, additional, Schulman, Sol, additional, Schulze, Harald, additional, Scully, Marie, additional, Seneviratne, Suranjith, additional, Sewell, Carrock, additional, Shamardina, Olga, additional, Shipley, Debbie, additional, Simeoni, Ilenia, additional, Sivapalaratnam, Suthesh, additional, Smith, Kenneth, additional, Sohal, Aman, additional, Southgate, Laura, additional, Staines, Simon, additional, Staples, Emily, additional, Stauss, Hans, additional, Stein, Penelope, additional, Stephens, Jonathan, additional, Stirrups, Kathleen, additional, Stock, Sophie, additional, Suntharalingam, Jay, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Yvonne, additional, Thachil, Jecko, additional, Thaventhiran, James, additional, Thomas, Ellen, additional, Thomas, Moira, additional, Thompson, Dorothy, additional, Thrasher, Adrian, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Toshner, Mark, additional, Treacy, Carmen, additional, Trembath, Richard, additional, Tuna, Salih, additional, Turek, Wojciech, additional, Turro, Ernest, additional, Van Geet, Chris, additional, Veltman, Marijke, additional, von Ziegenweldt, Julie, additional, Vonk Noordegraaf, Anton, additional, Wanjiku, Ivy, additional, Warner, Timothy Q., additional, Watkins, Hugh, additional, Webster, Andrew, additional, Welch, Steve, additional, Westbury, Sarah, additional, Wharton, John, additional, Whitehorn, Deborah, additional, Wilkins, Martin, additional, Willcocks, Lisa, additional, Williamson, Catherine, additional, Woods, Geoffrey, additional, Wort, John, additional, Yeatman, Nigel, additional, Yong, Patrick, additional, Young, Tim, additional, and Yu, Ping, additional

Published
2019
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38. TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

Author

Ngoh, Adeline, Bras, Jose, Guerreiro, Rita, McTague, Amy, Ng, Joanne, Meyer, Esther, Chong, W. Kling, Boyd, Stewart, MacLellan, Linda, Kirkpatrick, Martin, and Kurian, Manju A

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, lcsh:Diseases of the musculoskeletal system, TBC1D24, Case Reports, lcsh:RC925-935, 030217 neurology & neurosurgery, myoclonus, lcsh:Neurology. Diseases of the nervous system, lcsh:RC346-429, 030304 developmental biology, 3. Good health
Abstract

Background: Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus. Case Report: A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in TBC1D24, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G>A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6). Discussion: We propose that TBC1D24-related diseases should be in the differential diagnosis for children with polymyoclonus., Tremor and Other Hyperkinetic Movements, Tremor and Other Hyperkinetic Movements

Published
2017

39. GNAO1 encephalopathy

Author

Danti, Federica Rachele, Galosi, Serena, Romani, Marta, Montomoli, Martino, Carss, Keren J., Raymond, F. Lucy, Parrini, Elena, Bianchini, Claudia, McShane, Tony, Dale, Russell C., Mohammad, Shekeeb S., Shah, Ubaid, Mahant, Neil, Ng, Joanne, McTague, Amy, Samanta, Rajib, Vadlamani, Gayatri, Valente, Enza Maria, Leuzzi, Vincenzo, Kurian, Manju A., and Guerrini, Renzo

Subjects
Article
Abstract

Objective: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Results: Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

Published
2017

40. Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate.

Author

Sanchis‐Juan, Alba, Hasenahuer, Marcia A., Baker, James A., McTague, Amy, Barwick, Katy, Kurian, Manju A., Duarte, Sofia T., Carss, Keren J., Thornton, Janet, and Raymond, F. Lucy

Subjects
MISSENSE mutation, MEMBRANE proteins, PROTEIN analysis, NEUROLOGICAL disorders, GATES, IDENTIFICATION
Abstract

Background: Cys‐loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in GABRA2, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in GABRA2 in a patient with EIEE and performed protein structural analysis of the seven variants. Methods: The novel variant was identified by trio whole‐genome sequencing. We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys‐loop receptors. Additionally, we studied the distribution of disease‐associated variants in the transmembrane helices of these proteins. Results: The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter‐subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys‐loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore‐lining helix, consistent with this region being highly constrained for variation in control populations. Conclusion: Our study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations. [ABSTRACT FROM AUTHOR]

Published
2020
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41. The expanding spectrum of movement disorders in genetic epilepsies.

Author

Papandreou, Apostolos, Danti, Federica Rachele, Spaull, Robert, Leuzzi, Vincenzo, Mctague, Amy, and Kurian, Manju A

Subjects
GENETIC disorders, EPILEPSY, DYSKINESIAS, HUMAN chromosome abnormality diagnosis, SEIZURES (Medicine), MOVEMENT disorders, SIDE effects of anticonvulsants, NEUROLOGY
Abstract

An ever-increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the 'genetic epilepsy-dyskinesia' spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease-specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. WHAT THIS PAPER ADDS: Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required. [ABSTRACT FROM AUTHOR]

Published
2020
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42. De novo variants in SNAP25cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie-José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Van Ziffle, Jessica, Wadley, Alexandrea F., Wagner, Matias, Wigby, Kristen, Wortmann, Saskia B., Zarate, Yuri A., Møller, Rikke S., Lemke, Johannes R., and Platzer, Konrad

Abstract

This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Published
2021
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43. GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy

Author

Papandreou, Apostolos, McTague, Amy, Trump, Natalie, Ambegaonkar, Gautam, Ngoh, Adeline, Meyer, Esther, Scott, Richard H, and Kurian, Manju A

Subjects
Male, Epilepsy, Child, Preschool, Developmental Disabilities, Mutation, Humans, Infant, Case Report, Electroencephalography, Age of Onset, Receptors, GABA-A, Spasms, Infantile
Abstract

The gamma‐aminobutyric acid type A receptor β3 gene (GABRB3) encodes the β3‐subunit of the gamma‐aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signalling within the central nervous system. Recently, GABRB3 mutations have been identified in a few patients with infantile spasms and Lennox–Gastaut syndrome. We report the clinical and electrographic features of a novel case of GABRB3‐related early‐onset epileptic encephalopathy. Our patient presented with neonatal hypotonia and feeding difficulties, then developed pharmacoresistant epileptic encephalopathy, characterized by multiple seizure types from 3 months of age. Electroencephalography demonstrated ictal generalized and interictal multifocal epileptiform abnormalities. Using a SureSelectXT custom multiple gene panel covering 48 early infantile epileptic encephalopathy/developmental delay genes, a novel de novo GABRB3 heterozygous missense mutation, c.860C>T (p.Thr287Ile), was identified and confirmed on Sanger sequencing. GABRB3 is an emerging cause of early‐onset epilepsy. Novel genetic technologies, such as whole‐exome/genome sequencing and multiple gene panels, will undoubtedly identify further cases, allowing more detailed electroclinical delineation of the GABRB3‐related genotypic and phenotypic spectra., This article is commented on by Pearl on pages 330–331 of this issue.

Published
2015

44. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Author

Stödberg, Tommy, McTague, Amy, Ruiz, Arnaud J., Hirata, Hiromi, Zhen, Juan, Long, Philip, Farabella, Irene, Meyer, Esther, Kawahara, Atsuo, Vassallo, Grace, Stivaros, Stavros M., Bjursell, Magnus K., Stranneheim, Henrik, Tigerschiöld, Stephanie, Persson, Bengt, Bangash, Iftikhar, Das, Krishna, Hughes, Deborah, Lesko, Nicole, Lundeberg, Joakim, Scott, Rod C., Poduri, Annapurna, Scheffer, Ingrid E., Smith, Holly, Gissen, Paul, Schorge, Stephanie, Reith, Maarten E. A., Topf, Maya, Kullmann, Dimitri M., Harvey, Robert J., Wedell, Anna, and Kurian, Manju A.

Subjects
Male, Neurons, Patch-Clamp Techniques, Symporters, Cell- och molekylärbiologi, Immunoblotting, Infant, Pediatrik, Neural Inhibition, Sequence Analysis, DNA, Zebrafish Proteins, bcs, Pediatrics, Article, Pedigree, HEK293 Cells, Chlorides, Child, Preschool, Mutation, Animals, Humans, Epilepsies, Partial, Child, Zebrafish, Cell and Molecular Biology
Abstract

The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy., The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding gene SLC12A5, which impair normal synaptic function associated with early-onset epilepsy.

Published
2015

45. RARS 2 mutations in a sibship with infantile spasms

Author

Ngoh, Adeline, primary, Bras, Jose, additional, Guerreiro, Rita, additional, Meyer, Esther, additional, McTague, Amy, additional, Dawson, Eleanor, additional, Mankad, Kshitij, additional, Gunny, Roxana, additional, Clayton, Peter, additional, Mills, Philippa B., additional, Thornton, Rachel, additional, Lai, Ming, additional, Forsyth, Robert, additional, and Kurian, Manju A., additional

Published
2016
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48. Correction to: De novo variants in SNAP25cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie-José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Van Ziffle, Jessica, Wadley, Alexandrea F., Wagner, Matias, Wigby, Kristen, Wortmann, Saskia B., Zarate, Yuri A., Møller, Rikke S., Lemke, Johannes R., and Platzer, Konrad

Published
2021
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49. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy

Author

McTague, Amy, Nair, Umesh, Malhotra, Shalini, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngho, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William P., Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. “Kling ”, Cross, J.Helen, Topf, M, Petrou, S, Kurian, Manju A., McTague, Amy, Nair, Umesh, Malhotra, Shalini, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngho, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William P., Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. “Kling ”, Cross, J.Helen, Topf, M, Petrou, S, and Kurian, Manju A.

Abstract

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

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50. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy

Author

McTague, Amy, Nair, Umesh, Malhotra, Sony, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngho, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William, Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. “Kling ”, Cross, J.Helen, Topf, Maya, Petrou, Steven, Kurian, Manju A., McTague, Amy, Nair, Umesh, Malhotra, Sony, Meyer, Esther, Trump, Natalie, Gazina, Elena V., Papandreou, Apostolos, Ngho, Adeline, Ackermann, Sally, Ambegaonkar, Gautam, Appleton, Richard, Desurkar, Archana, Eltze, Christin, Kneen, Rachel, Kumar, Ajith V., Lascelles, Karine, Montgomery, Tara, Ramesh, Venkateswaran, Samanta, Rajib, Scott, Richard H., Tan, Jeen, Whitehouse, William, Poduri, Annapurna, Scheffer, Ingrid E., Chong, W.K. “Kling ”, Cross, J.Helen, Topf, Maya, Petrou, Steven, and Kurian, Manju A.

Abstract

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

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