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1. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Published
2024
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2. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Commerce, Management, Tourism and Services, SPARK Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

3. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Basic Helix-Loop-Helix Transcription Factors, CCCTC-Binding Factor, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein U, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel, Male, Mutation, Neurodevelopmental Disorders, RNA-Binding Proteins, Repressor Proteins, Transcription Factors, SPARK Consortium
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

Published
2020

5. De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome

Author

Palmer, Elizabeth E, Hong, Seungbeom, Zahrani, Fatema Al, Hashem, Mais O, Aleisa, Fajr A, Ahmed, Heba M Jalal, Kandula, Tejaswi, Macintosh, Rebecca, Minoche, Andre E, Puttick, Clare, Gayevskiy, Velimir, Drew, Alexander P, Cowley, Mark J, Dinger, Marcel, Rosenfeld, Jill A, Xiao, Rui, Cho, Megan T, Yakubu, Suliat F, Henderson, Lindsay B, Sacoto, Maria J Guillen, Begtrup, Amber, Hamad, Muddathir, Shinawi, Marwan, Andrews, Marisa V, Jones, Marilyn C, Lindstrom, Kristin, Bristol, Ruth E, Kayani, Saima, Snyder, Molly, Villanueva, María Mercedes, Schteinschnaider, Angeles, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Roscioli, Tony, Kirk, Edwin P, Bye, Ann, Merzaban, Jasmeen, Jaremko, Łukasz, Jaremko, Mariusz, Sachdev, Rani K, Alkuraya, Fowzan S, and Arold, Stefan T

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Neurodegenerative, Rare Diseases, Genetics, Pediatric, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Amino Acid Motifs, Child, Child, Preschool, Female, Genetic Variation, Humans, Infant, Male, Nerve Tissue Proteins, Neurocognitive Disorders, Phenotype, Prognosis, Repetitive Sequences, Nucleic Acid, Syndrome, HX repeat, allelic disorders, developmental delay, dysmorphic, intellectual disability, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Published
2019

8. ‘High hopes for treatment’: Australian stakeholder perspectives of the clinical translation of advanced neurotherapeutics for rare neurological diseases

Author

Nguyen, Christina Q., primary, Kariyawasam, Didu S. T., additional, Ngai, Tsz Shun Jason, additional, Nguyen, James, additional, Alba‐Concepcion, Kristine, additional, Grattan, Sarah E., additional, Palmer, Elizabeth E., additional, Hetherington, Kate, additional, Wakefield, Claire E., additional, Dale, Russell C., additional, Woolfenden, Sue, additional, Mohammad, Shekeeb, additional, and Farrar, Michelle A., additional

Published
2024
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9. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M.S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Published
2021
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11. De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Author

Nabais Sá, Maria J., Jensik, Philip J., McGee, Stacey R., Parker, Michael J., Lahiri, Nayana, McNeil, Evan P., Kroes, Hester Y., Hagerman, Randi J., Harrison, Rachel E., Montgomery, Tara, Splitt, Miranda, Palmer, Elizabeth E., Sachdev, Rani K., Mefford, Heather C., Scott, Abbey A., Martinez-Agosto, Julian A., Lorenz, Rüdiger, Orenstein, Naama, Berg, Jonathan N., Amiel, Jeanne, Heron, Delphine, Keren, Boris, Cobben, Jan-Maarten, Menke, Leonie A., Marco, Elysa J., Graham, Jr, John M., Pierson, Tyler Mark, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Manzini, M. Chiara, Cauley, Edmund S., Colombo, Roberto, Odent, Sylvie, Dubourg, Christele, Phornphutkul, Chanika, de Brouwer, Arjan P. M., de Vries, Bert B. A., and Vulto-vanSilfhout, Anneke T.

Published
2019
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12. Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Author

Torti, Erin, Keren, Boris, Palmer, Elizabeth E., Zhu, Zehua, Afenjar, Alexandra, Anderson, Ilse. J., Andrews, Marisa V., Atkinson, Celia, Au, Margaret, Berry, Susan A., Bowling, Kevin M., Boyle, Jackie, Buratti, Julien, Cathey, Sara S., Charles, Perrine, Cogne, Benjamin, Courtin, Thomas, Escobar, Luis F., Finley, Sabra Ledare, Graham, Jr., John M., Grange, Dorothy K., Heron, Delphine, Hewson, Stacy, Hiatt, Susan M., Hibbs, Kathleen A., Jayakar, Parul, Kalsner, Louisa, Larcher, Lise, Lesca, Gaetan, Mark, Paul R., Miller, Kathryn, Nava, Caroline, Nizon, Mathilde, Pai, G. Shashidhar, Pappas, John, Parsons, Gretchen, Payne, Katelyn, Putoux, Audrey, Rabin, Rachel, Sabatier, Isabelle, Shinawi, Marwan, Shur, Natasha, Skinner, Steven A., Valence, Stephanie, Warren, Hannah, Whalen, Sandra, Crunk, Amy, Douglas, Ganka, Monaghan, Kristin G., Person, Richard E., Willaert, Rebecca, Solomon, Benjamin D., and Juusola, Jane

Published
2019
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13. Quality of life in caregivers of a child with a developmental and epileptic encephalopathy.

Author

Robertson, Eden G., Kelada, Lauren, Best, Stephanie, Goranitis, Ilias, Pierce, Kristine, Roberts, Natalie J, Sachdev, Rani, Le Marne, Fleur, Macintosh, Rebecca, Beavis, Erin, Bye, Annie, and Palmer, Elizabeth E.

Subjects
QUALITY of life, CHILDREN with epilepsy, CAREGIVERS, HEALTH literacy, BRAIN diseases, SERVICES for caregivers
Abstract

Aim: To explore the relationship between social care‐related quality of life (SCrQoL) for caregivers of a child with a developmental and epileptic encephalopathy (DEE; such as SCN2A and Dravet syndrome) and health literacy, illness perceptions, and caregiver activation. Method: As part of a larger pre‐post pilot study of an information linker service, caregivers completed a baseline questionnaire which included demographics and measures to assess SCrQoL, health literacy, illness perceptions, and caregiver activation. We used Spearman's Rho to determine relationships between variables. Results: Seventy‐two caregivers completed the questionnaire. Total SCrQoL varied widely, ranging from an 'ideal state' to 'high needs state'. Caregivers most frequently reported high needs regarding doing activities they enjoy and looking after themselves. Total SCrQoL was correlated with cognitive (r[70] = −0.414, p < 0.000) and emotional representations of illness (r[70] = −0.503, p < 0.000), but not coherence (r = −0.075, p = 0.529). Total SCrQoL was not correlated with health literacy (r[70] = 0.125, p = 0.295) or caregiver activation (r[70] = 0.181, p = 0.127). Interpretation: Future research should explore whether interventions that help caregivers cognitively reframe the negative experiences of having a child with a DEE, and support them to partake in activities they enjoy, boost their SCrQoL. What this paper adds: Caregiver social care‐related quality of life (SCrQoL) varied widely, from 'ideal state' to 'high needs state'.Most common high needs were doing enjoyable activities and self‐care.Caregivers with higher SCrQoL may perceive their child's illness as less threatening.SCrQoL does not appear to be related to caregiver activation in this sample. [ABSTRACT FROM AUTHOR]

Published
2024
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14. 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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15. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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16. ‘Advocacy groups are the connectors’: Experiences and contributions of rare disease patient organization leaders in advanced neurotherapeutics

Author

Nguyen, Christina Q., primary, Kariyawasam, Didu, additional, Alba‐Concepcion, Kristine, additional, Grattan, Sarah, additional, Hetherington, Kate, additional, Wakefield, Claire E., additional, Woolfenden, Susan, additional, Dale, Russell C., additional, Palmer, Elizabeth E., additional, and Farrar, Michelle A., additional

Published
2022
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17. Acceptability and feasibility of an online information linker service for caregivers who have a child with genetic epilepsy: a mixed-method pilot study protocol

Author

Robertson, Eden G, primary, Kelada, Lauren, additional, Best, Stephanie, additional, Goranitis, I, additional, Grainger, Natalie, additional, Le Marne, Fleur, additional, Pierce, Kristine, additional, Nevin, Suzanne M, additional, Macintosh, Rebecca, additional, Beavis, Erin, additional, Sachdev, Rani, additional, Bye, Annie, additional, and Palmer, Elizabeth E, additional

Published
2022
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18. 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

20. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Author

Bournazos, Adam M., primary, Riley, Lisa G., additional, Bommireddipalli, Shobhana, additional, Ades, Lesley, additional, Akesson, Lauren S., additional, Al-Shinnag, Mohammad, additional, Alexander, Stephen I., additional, Archibald, Alison D., additional, Balasubramaniam, Shanti, additional, Berman, Yemima, additional, Beshay, Victoria, additional, Boggs, Kirsten, additional, Bojadzieva, Jasmina, additional, Brown, Natasha J., additional, Bryen, Samantha J., additional, Buckley, Michael F., additional, Chong, Belinda, additional, Davis, Mark R., additional, Dawes, Ruebena, additional, Delatycki, Martin, additional, Donaldson, Liz, additional, Downie, Lilian, additional, Edwards, Caitlin, additional, Edwards, Matthew, additional, Engel, Amanda, additional, Ewans, Lisa J., additional, Faiz, Fathimath, additional, Fennell, Andrew, additional, Field, Michael, additional, Freckmann, Mary-Louise, additional, Gallacher, Lyndon, additional, Gear, Russell, additional, Goel, Himanshu, additional, Goh, Shuxiang, additional, Goodwin, Linda, additional, Hanna, Bernadette, additional, Harraway, James, additional, Higgins, Megan, additional, Ho, Gladys, additional, Hopper, Bruce K., additional, Horton, Ari E., additional, Hunter, Matthew F., additional, Huq, Aamira J., additional, Josephi-Taylor, Sarah, additional, Joshi, Himanshu, additional, Kirk, Edwin, additional, Krzesinski, Emma, additional, Kumar, Kishore R., additional, Lemckert, Frances, additional, Leventer, Richard J., additional, Lindsey-Temple, Suzanna E., additional, Lunke, Sebastian, additional, Ma, Alan, additional, Macaskill, Steven, additional, Mallawaarachchi, Amali, additional, Marty, Melanie, additional, Marum, Justine E., additional, McCarthy, Hugh J., additional, Menezes, Manoj P., additional, McLean, Alison, additional, Milnes, Di, additional, Mohammad, Shekeeb, additional, Mowat, David, additional, Niaz, Aram, additional, Palmer, Elizabeth E., additional, Patel, Chirag, additional, Patel, Shilpan G., additional, Phelan, Dean, additional, Pinner, Jason R., additional, Rajagopalan, Sulekha, additional, Regan, Matthew, additional, Rodgers, Jonathan, additional, Rodrigues, Miriam, additional, Roxburgh, Richard H., additional, Sachdev, Rani, additional, Roscioli, Tony, additional, Samarasekera, Ruvishani, additional, Sandaradura, Sarah A., additional, Savva, Elena, additional, Schindler, Tim, additional, Shah, Margit, additional, Sinnerbrink, Ingrid B., additional, Smith, Janine M., additional, Smith, Richard J., additional, Springer, Amanda, additional, Stark, Zornitza, additional, Strom, Samuel P., additional, Sue, Carolyn M., additional, Tan, Kenneth, additional, Tan, Tiong Y., additional, Tantsis, Esther, additional, Tchan, Michel C., additional, Thompson, Bryony A., additional, Trainer, Alison H., additional, van Spaendonck-Zwarts, Karin, additional, Walsh, Rebecca, additional, Warwick, Linda, additional, White, Stephanie, additional, White, Susan M., additional, Williams, Mark G., additional, Wilson, Meredith J., additional, Wong, Wui Kwan, additional, Wright, Dale C., additional, Yap, Patrick, additional, Yeung, Alison, additional, Young, Helen, additional, Jones, Kristi J., additional, Bennetts, Bruce, additional, Cooper, Sandra T., additional, Abdulrasool, Ghusoon, additional, Al Eryani, Ghamdan, additional, Arts, Peer, additional, Bagnall, Richard, additional, Baker, Naomi L., additional, Barnett, Christopher, additional, Beecroft, Sarah, additional, Berbic, Marina, additional, Black, Michael, additional, Blackburn, Jim, additional, Blombery, Piers, additional, Bournazos, Adam M., additional, Branford, Susan, additional, Breen, Jimmy, additional, Burnett, Leslie, additional, Canson, Daffodil, additional, Cheong, Pak, additional, Chew, Edward, additional, Christodoulou, John, additional, Chung, Seo-Kyung, additional, Clark, Mike, additional, Cliffe, Corrina, additional, Cole, Melissa, additional, Collins, Felicity, additional, Compton, Alison, additional, Cooper, Antony, additional, Corbett, Mark, additional, Cowley, Mark, additional, Dudding, Tracy, additional, Eggers, Stefanie, additional, Eyras, Eduardo, additional, Fernandez, Miriam Fanjul, additional, Fellowes, Andrew, additional, Fleischer, Ron, additional, Folland, Chiara, additional, Fox, Lucy, additional, Gaff, Clara, additional, Galea, Melanie, additional, Ghaoui, Roula, additional, Gornanitis, Ilias, additional, Ha, Thuong, additional, Hayashi, Rippei, additional, Hayes, Ian, additional, Henderson, Alex, additional, Hesson, Luke, additional, Heyer, Erin, additional, Hildebrand, Michael, additional, Hipwell, Michael, additional, Hoskins, Cass, additional, Jackson, Matilda, additional, James, Paul, additional, Wong, Justin Jong-Leong, additional, Kassahn, Karin, additional, Kaub, Peter, additional, Kevin, Lucy, additional, Kumble, Smitha, additional, Kummerfeld, Sarah, additional, Laing, Nigel, additional, Lau, Chiyan, additional, Lee, Eric, additional, Leighton, Sarah, additional, Lundie, Ben, additional, Mayoh, Chelsea, additional, McGaughran, Julie, additional, McPhillips, Mary, additional, Meldrum, Cliff, additional, Middleton, Edwina, additional, Mina, Kym, additional, Nisselle, Amy, additional, Oates, Emily, additional, Oshlack, Alicia, additional, Parasivam, Gayathri, additional, Parsons, Michael, additional, Quinn, Michael, additional, Rasko, John, additional, Ravenscroft, Gina, additional, Ravine, Anja, additional, Recsei, Krista, additional, Rehn, Jacqueline, additional, Robertson, Stephen, additional, Ronan, Anne, additional, Ryland, Georgina, additional, Sadedin, Simon, additional, Schreiber, Andreas, additional, Scott, Hamish, additional, Scott, Rodney, additional, Semsarian, Christopher, additional, Simons, Cas, additional, Singer, Emma, additional, Smyth, Renee, additional, Spurdle, Amanda, additional, Sullivan, Patricia, additional, Sundercombe, Samantha, additional, Thorburn, David, additional, Toubia, John, additional, Trent, Ronald, additional, Tudini, Emma, additional, Voneague, Irina, additional, Waddell, Leigh, additional, Walker, Logan, additional, Wallis, Mathew, additional, Warnock, Nick, additional, Weatheritt, Robert, additional, White, Deborah, additional, Winship, Ingrid, additional, Worgan, Lisa, additional, Wu, Kathy, additional, and Ziolowski, Andrew, additional

Published
2022
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21. Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.

Author

Scheffer, Ingrid E., Bennett, Caitlin A., Gill, Deepak, de Silva, Michelle G., Boggs, Kirsten, Marum, Justine, Baker, Naomi, Palmer, Elizabeth E., Howell, Katherine B., Andrews, Ian, Antony, Jayne, Ardern‐Holmes, Simone, Bye, Ann M, Cardamone, Michael, Chelakkadan, Shabeed, Clark, Damian, Curnow, Sarah R, Dabscheck, Gabriel, Fahey, Michael C, and Freeman, Jeremy L

Subjects
PEOPLE with epilepsy, GENOMICS, MOLECULAR diagnosis, CHILD care, CLINICAL medicine, EPILEPSY, PSYCHOGENIC nonepileptic seizures
Abstract

Aim: To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Method: Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Results: Of the 103 patients recruited (54 males, 49 females; aged 2 weeks–17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high‐density chromosomal microarray testing. Interpretation: We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. [ABSTRACT FROM AUTHOR]

Published
2023
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23. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum

Author

Palmer, Elizabeth E., primary, Whitton, Chloe, additional, Hashem, Mais O., additional, Clark, Robin D., additional, Ramanathan, Subhadra, additional, Starr, Lois J., additional, Velasco, Danita, additional, De Dios, John Karl, additional, Singh, Emily, additional, Cormier‐Daire, Valerie, additional, Chopra, Maya, additional, Rodan, Lance H., additional, Nellaker, Christoffer, additional, Lakhani, Shenela, additional, Mallack, Eric J., additional, Panzer, Karin, additional, Sidhu, Alpa, additional, Wentzensen, Ingrid M., additional, Lacombe, Didier, additional, Michaud, Vincent, additional, and Alkuraya, Fowzan S., additional

Published
2021
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24. ATP1A2-and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria

Author

Vetro, Annalisa, Nielsen, Hang N., Holm, Rikke, Hevner, Robert F., Parrini, Elena, Powis, Zoe, Møller, Rikke S., Bellan, Cristina, Simonati, Alessandro, Lesca, Gaétan, Helbig, Katherine L., Palmer, Elizabeth E., Mei, Davide, Ballardini, Elisa, Van Haeringen, Arie, Syrbe, Steffen, Leuzzi, Vincenzo, Cioni, Giovanni, Curry, Cynthia J., Costain, Gregory, Santucci, Margherita, Chong, Karen, Mancini, Grazia M.S., Clayton-Smith, Jill, Bigoni, Stefania, Scheffer, Ingrid E., Dobyns, William B., Vilsen, Bente, Guerrini, Renzo, Vetro, Annalisa, Nielsen, Hang N., Holm, Rikke, Hevner, Robert F., Parrini, Elena, Powis, Zoe, Møller, Rikke S., Bellan, Cristina, Simonati, Alessandro, Lesca, Gaétan, Helbig, Katherine L., Palmer, Elizabeth E., Mei, Davide, Ballardini, Elisa, Van Haeringen, Arie, Syrbe, Steffen, Leuzzi, Vincenzo, Cioni, Giovanni, Curry, Cynthia J., Costain, Gregory, Santucci, Margherita, Chong, Karen, Mancini, Grazia M.S., Clayton-Smith, Jill, Bigoni, Stefania, Scheffer, Ingrid E., Dobyns, William B., Vilsen, Bente, and Guerrini, Renzo

Abstract

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and

Published
2021

25. RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

Author

Palmer, Elizabeth E., primary, Carroll, Renee, additional, Shaw, Marie, additional, Kumar, Raman, additional, Minoche, Andre E., additional, Leffler, Melanie, additional, Murray, Lucinda, additional, Macintosh, Rebecca, additional, Wright, Dale, additional, Troedson, Chris, additional, McKenzie, Fiona, additional, Townshend, Sharron, additional, Ward, Michelle, additional, Nawaz, Urwah, additional, Ravine, Anja, additional, Runke, Cassandra K., additional, Thorland, Erik C., additional, Hummel, Marybeth, additional, Foulds, Nicola, additional, Pichon, Olivier, additional, Isidor, Bertrand, additional, Le Caignec, Cédric, additional, Demeer, Bénédicte, additional, Andrieux, Joris, additional, Albarazi, Salam Hadah, additional, Bye, Ann, additional, Sachdev, Rani, additional, Kirk, Edwin P., additional, Cowley, Mark J., additional, Field, Mike, additional, and Gecz, Jozef, additional

Published
2020
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27. Psychosocial impact of genetic testing on parents of children with developmental and epileptic encephalopathy.

Author

Nevin, Suzanne M, Wakefield, Claire E, Barlow‐Stewart, Kristine, McGill, Brittany C, Bye, Ann, Palmer, Elizabeth E, Dale, Russell C, Gill, Deepak, Kothur, Kavitha, Boggs, Kirsten, Le Marne, Fleur, Beavis, Erin, Macintosh, Rebecca, and Sachdev, Rani

Subjects
GENETIC testing, PARENTS, CHILDREN with epilepsy, QUALITY of life, BRAIN diseases, PSYCHOLOGICAL stress
Abstract

Aim: To investigate the psychosocial impact of genetic testing for childhood‐onset developmental and epileptic encephalopathies (DEEs) in order to identify parents' information and support needs. Method: In this mixed‐methods study, we conducted in‐depth semi‐structured interviews with parents (n=25) of children, recruited from the Sydney Children's Hospital Network, Australia, who had received genetic testing. Thematic saturation was reached; interviews were transcribed, deidentified, line‐by‐line coded, and thematically analysed by three coders, using an inductive approach. We also quantitatively assessed the impact of genetic testing on quality of life outcomes and parents' satisfaction with genetics services. Results: Qualitative and quantitative analysis revealed that compassionate genetic counselling and consistent clinician–parent partnerships facilitated parents' capacity to process their child's genetic diagnosis. Parents believed that a sparsity of diagnosis‐specific information to contextualize their child's genetic DEE, combined with limited psychosocial resources to support coping with ongoing prognostic uncertainty, contributed to chronic psychological stress. Access to diagnosis‐specific resources and peer support was considered necessary to support parents in communicating their child's genetic DEE and to reduce social isolation. Interpretation: Integrated psychosocial resources, including tailored psychological supports, diagnosis‐specific information, and peer‐to‐peer supports, are priority areas to complement genetic services. podcast : (https://youtu.be/3tFjqndfQuI) This original article is commented by Tumiene on page 13 of this issue. [ABSTRACT FROM AUTHOR]

Published
2022
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28. Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing

Author

Field, Michael, primary, Dudding-Byth, Tracy, additional, Arpone, Marta, additional, Baker, Emma K., additional, Aliaga, Solange M., additional, Rogers, Carolyn, additional, Hickerton, Chriselle, additional, Francis, David, additional, Phelan, Dean G., additional, Palmer, Elizabeth E., additional, Amor, David J., additional, Slater, Howard, additional, Bretherton, Lesley, additional, Ling, Ling, additional, and Godler, David E., additional

Published
2019
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29. PIGGvariant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M.S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Abstract

Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Published
2021
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30. Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms

Author

Kumar, Kishore R., primary, Wali, Gautam, additional, Davis, Ryan L., additional, Mallawaarachchi, Amali C., additional, Palmer, Elizabeth E., additional, Gayevskiy, Velimir, additional, Minoche, Andre E., additional, Veivers, David, additional, Dinger, Marcel E., additional, Mackay-Sim, Alan, additional, Cowley, Mark J., additional, and Sue, Carolyn M., additional

Published
2018
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31. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author

Cheng, Hanyin, primary, Dharmadhikari, Avinash V., additional, Varland, Sylvia, additional, Ma, Ning, additional, Domingo, Deepti, additional, Kleyner, Robert, additional, Rope, Alan F., additional, Yoon, Margaret, additional, Stray-Pedersen, Asbjørg, additional, Posey, Jennifer E., additional, Crews, Sarah R., additional, Eldomery, Mohammad K., additional, Akdemir, Zeynep Coban, additional, Lewis, Andrea M., additional, Sutton, Vernon R., additional, Rosenfeld, Jill A., additional, Conboy, Erin, additional, Agre, Katherine, additional, Xia, Fan, additional, Walkiewicz, Magdalena, additional, Longoni, Mauro, additional, High, Frances A., additional, van Slegtenhorst, Marjon A., additional, Mancini, Grazia M.S., additional, Finnila, Candice R., additional, van Haeringen, Arie, additional, den Hollander, Nicolette, additional, Ruivenkamp, Claudia, additional, Naidu, Sakkubai, additional, Mahida, Sonal, additional, Palmer, Elizabeth E., additional, Murray, Lucinda, additional, Lim, Derek, additional, Jayakar, Parul, additional, Parker, Michael J., additional, Giusto, Stefania, additional, Stracuzzi, Emanuela, additional, Romano, Corrado, additional, Beighley, Jennifer S., additional, Bernier, Raphael A., additional, Küry, Sébastien, additional, Nizon, Mathilde, additional, Corbett, Mark A., additional, Shaw, Marie, additional, Gardner, Alison, additional, Barnett, Christopher, additional, Armstrong, Ruth, additional, Kassahn, Karin S., additional, Van Dijck, Anke, additional, Vandeweyer, Geert, additional, Kleefstra, Tjitske, additional, Schieving, Jolanda, additional, Jongmans, Marjolijn J., additional, de Vries, Bert B.A., additional, Pfundt, Rolph, additional, Kerr, Bronwyn, additional, Rojas, Samantha K., additional, Boycott, Kym M., additional, Person, Richard, additional, Willaert, Rebecca, additional, Eichler, Evan E., additional, Kooy, R. Frank, additional, Yang, Yaping, additional, Wu, Joseph C., additional, Lupski, James R., additional, Arnesen, Thomas, additional, Cooper, Gregory M., additional, Chung, Wendy K., additional, Gecz, Jozef, additional, Stessman, Holly A.F., additional, Meng, Linyan, additional, and Lyon, Gholson J., additional

Published
2018
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32. A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures

Author

Gennarino, Vincenzo A., primary, Palmer, Elizabeth E., additional, McDonell, Laura M., additional, Wang, Li, additional, Adamski, Carolyn J., additional, Koire, Amanda, additional, See, Lauren, additional, Chen, Chun-An, additional, Schaaf, Christian P., additional, Rosenfeld, Jill A., additional, Panzer, Jessica A., additional, Moog, Ute, additional, Hao, Shuang, additional, Bye, Ann, additional, Kirk, Edwin P., additional, Stankiewicz, Pawel, additional, Breman, Amy M., additional, McBride, Arran, additional, Kandula, Tejaswi, additional, Dubbs, Holly A., additional, Macintosh, Rebecca, additional, Cardamone, Michael, additional, Zhu, Ying, additional, Ying, Kevin, additional, Dias, Kerith-Rae, additional, Cho, Megan T., additional, Henderson, Lindsay B., additional, Baskin, Berivan, additional, Morris, Paula, additional, Tao, Jiang, additional, Cowley, Mark J., additional, Dinger, Marcel E., additional, Roscioli, Tony, additional, Caluseriu, Oana, additional, Suchowersky, Oksana, additional, Sachdev, Rani K., additional, Lichtarge, Olivier, additional, Tang, Jianrong, additional, Boycott, Kym M., additional, Holder, J. Lloyd, additional, and Zoghbi, Huda Y., additional

Published
2018
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33. Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Author

Palmer, Elizabeth E., primary, Schofield, Deborah, additional, Shrestha, Rupendra, additional, Kandula, Tejaswi, additional, Macintosh, Rebecca, additional, Lawson, John A., additional, Andrews, Ian, additional, Sampaio, Hugo, additional, Johnson, Alexandra M., additional, Farrar, Michelle A., additional, Cardamone, Michael, additional, Mowat, David, additional, Elakis, George, additional, Lo, William, additional, Zhu, Ying, additional, Ying, Kevin, additional, Morris, Paula, additional, Tao, Jiang, additional, Dias, Kerith-Rae, additional, Buckley, Michael, additional, Dinger, Marcel E., additional, Cowley, Mark J., additional, Roscioli, Tony, additional, Kirk, Edwin P., additional, Bye, Ann, additional, and Sachdev, Rani K., additional

Published
2018
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34. A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Author

Palmer, Elizabeth E., primary, Kumar, Raman, additional, Gordon, Christopher T., additional, Shaw, Marie, additional, Hubert, Laurence, additional, Carroll, Renee, additional, Rio, Marlène, additional, Murray, Lucinda, additional, Leffler, Melanie, additional, Dudding-Byth, Tracy, additional, Oufadem, Myriam, additional, Lalani, Seema R., additional, Lewis, Andrea M., additional, Xia, Fan, additional, Tam, Allison, additional, Webster, Richard, additional, Brammah, Susan, additional, Filippini, Francesca, additional, Pollard, John, additional, Spies, Judy, additional, Minoche, Andre E., additional, Cowley, Mark J., additional, Risen, Sarah, additional, Powell-Hamilton, Nina N., additional, Tusi, Jessica E., additional, Immken, LaDonna, additional, Nagakura, Honey, additional, Bole-Feysot, Christine, additional, Nitschké, Patrick, additional, Garrigue, Alexandrine, additional, de Saint Basile, Geneviève, additional, Kivuva, Emma, additional, Scott, Richard H., additional, Rendon, Augusto, additional, Munnich, Arnold, additional, Newman, William, additional, Kerr, Bronwyn, additional, Besmond, Claude, additional, Rosenfeld, Jill A., additional, Amiel, Jeanne, additional, Field, Michael, additional, and Gecz, Jozef, additional

Published
2017
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35. Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum

Author

Smogavec, Mateja, Cleall, Alison, Hoyer, Juliane, Lederer, Damien, Nassogne, Marie-Cécile, Palmer, Elizabeth E., Deprez, Marie, Benoit, Valérie, Maystadt, Isabelle, Noakes, Charlotte, Leal, Alejandro, Shaw, Marie, Gecz, Jozef, Raymond, Lucy, Reis, André, Shears, Deborah, Brockmann, Knut, and Zweier, Christiane

Subjects
Medizinische Fakultät, ddc:610
Abstract

Background Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. Methods Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. Results We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. Conclusions By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.

Published
2016

36. Eight further individuals with intellectual disability and epilepsy carrying bi-allelicCNTNAP2aberrations allow delineation of the mutational and phenotypic spectrum

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Smogavec, Mateja, Cleall, Alison, Hoyer, Juliane, Lederer, Damien, Nassogne, Marie-Cécile, Palmer, Elizabeth E, Deprez, Marie, Benoit, Valérie, Maystadt, Isabelle, Noakes, Charlotte, Leal, Alejandro, Shaw, Marie, Gecz, Jozef, Raymond, Lucy, Reis, André, Shears, Deborah, Brockmann, Knut, Zweier, Christiane, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Smogavec, Mateja, Cleall, Alison, Hoyer, Juliane, Lederer, Damien, Nassogne, Marie-Cécile, Palmer, Elizabeth E, Deprez, Marie, Benoit, Valérie, Maystadt, Isabelle, Noakes, Charlotte, Leal, Alejandro, Shaw, Marie, Gecz, Jozef, Raymond, Lucy, Reis, André, Shears, Deborah, Brockmann, Knut, and Zweier, Christiane

Abstract

BACKGROUND : Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. METHODS: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. RESULTS: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. CONCLUSIONS: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.

Published
2016

37. Eight further individuals with intellectual disability and epilepsy carrying bi-allelicCNTNAP2aberrations allow delineation of the mutational and phenotypic spectrum

Author

Smogavec, Mateja, primary, Cleall, Alison, additional, Hoyer, Juliane, additional, Lederer, Damien, additional, Nassogne, Marie-Cécile, additional, Palmer, Elizabeth E, additional, Deprez, Marie, additional, Benoit, Valérie, additional, Maystadt, Isabelle, additional, Noakes, Charlotte, additional, Leal, Alejandro, additional, Shaw, Marie, additional, Gecz, Jozef, additional, Raymond, Lucy, additional, Reis, André, additional, Shears, Deborah, additional, Brockmann, Knut, additional, and Zweier, Christiane, additional

Published
2016
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38. Neuronal deficiency ofARV1causes an autosomal recessive epileptic encephalopathy

Author

Palmer, Elizabeth E, primary, Jarrett, Kelsey E, additional, Sachdev, Rani K, additional, Al Zahrani, Fatema, additional, Hashem, Mais Omar, additional, Ibrahim, Niema, additional, Sampaio, Hugo, additional, Kandula, Tejaswi, additional, Macintosh, Rebecca, additional, Gupta, Rajat, additional, Conlon, Donna M., additional, Billheimer, Jeffrey T., additional, Rader, Daniel J., additional, Funato, Kouichi, additional, Walkey, Christopher J., additional, Lee, Chang Seok, additional, Loo, Christine, additional, Brammah, Susan, additional, Elakis, George, additional, Zhu, Ying, additional, Buckley, Michael, additional, Kirk, Edwin P, additional, Bye, Ann, additional, Alkuraya, Fowzan S., additional, Roscioli, Tony, additional, and Lagor, William R, additional

Published
2016
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39. De novo and biallelic DEAF1variants cause a phenotypic spectrum

Author

Nabais Sá, Maria J., Jensik, Philip J., McGee, Stacey R., Parker, Michael J., Lahiri, Nayana, McNeil, Evan P., Kroes, Hester Y., Hagerman, Randi J., Harrison, Rachel E., Montgomery, Tara, Splitt, Miranda, Palmer, Elizabeth E., Sachdev, Rani K., Mefford, Heather C., Scott, Abbey A., Martinez-Agosto, Julian A., Lorenz, Rüdiger, Orenstein, Naama, Berg, Jonathan N., Amiel, Jeanne, Heron, Delphine, Keren, Boris, Cobben, Jan-Maarten, Menke, Leonie A., Marco, Elysa J., Graham, John M., Pierson, Tyler Mark, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Manzini, M. Chiara, Cauley, Edmund S., Colombo, Roberto, Odent, Sylvie, Dubourg, Christele, Phornphutkul, Chanika, de Brouwer, Arjan P.M., de Vries, Bert B.A., and Vulto-vanSilfhout, Anneke T.

Abstract

To investigate the effect of different DEAF1variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

Published
2019
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40. Variants in TCF20in neurodevelopmental disability: description of 27 new patients and review of literature

Author

Torti, Erin, Keren, Boris, Palmer, Elizabeth E., Zhu, Zehua, Afenjar, Alexandra, Anderson, Ilse. J., Andrews, Marisa V., Atkinson, Celia, Au, Margaret, Berry, Susan A., Bowling, Kevin M., Boyle, Jackie, Buratti, Julien, Cathey, Sara S., Charles, Perrine, Cogne, Benjamin, Courtin, Thomas, Escobar, Luis F., Finley, Sabra Ledare, Graham, John M., Grange, Dorothy K., Heron, Delphine, Hewson, Stacy, Hiatt, Susan M., Hibbs, Kathleen A., Jayakar, Parul, Kalsner, Louisa, Larcher, Lise, Lesca, Gaetan, Mark, Paul R., Miller, Kathryn, Nava, Caroline, Nizon, Mathilde, Pai, G. Shashidhar, Pappas, John, Parsons, Gretchen, Payne, Katelyn, Putoux, Audrey, Rabin, Rachel, Sabatier, Isabelle, Shinawi, Marwan, Shur, Natasha, Skinner, Steven A., Valence, Stephanie, Warren, Hannah, Whalen, Sandra, Crunk, Amy, Douglas, Ganka, Monaghan, Kristin G., Person, Richard E., Willaert, Rebecca, Solomon, Benjamin D., and Juusola, Jane

Abstract

To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients.

Published
2019
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41. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Author

Kumar, Raman, primary, Corbett, Mark A., additional, van Bon, Bregje W.M., additional, Woenig, Joshua A., additional, Weir, Lloyd, additional, Douglas, Evelyn, additional, Friend, Kathryn L., additional, Gardner, Alison, additional, Shaw, Marie, additional, Jolly, Lachlan A., additional, Tan, Chuan, additional, Hunter, Matthew F., additional, Hackett, Anna, additional, Field, Michael, additional, Palmer, Elizabeth E., additional, Leffler, Melanie, additional, Rogers, Carolyn, additional, Boyle, Jackie, additional, Bienek, Melanie, additional, Jensen, Corinna, additional, Van Buggenhout, Griet, additional, Van Esch, Hilde, additional, Hoffmann, Katrin, additional, Raynaud, Martine, additional, Zhao, Huiying, additional, Reed, Robin, additional, Hu, Hao, additional, Haas, Stefan A., additional, Haan, Eric, additional, Kalscheuer, Vera M., additional, and Gecz, Jozef, additional

Published
2015
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43. ATP1A2- and ATP1A3- associated early profound epileptic encephalopathy and polymicrogyria

Author

Vetro, Annalisa, Nielsen, Hang N, Holm, Rikke, Hevner, Robert F, Parrini, Elena, Powis, Zoe, Møller, Rikke S, Bellan, Cristina, Simonati, Alessandro, Lesca, Gaétan, Helbig, Katherine L, Palmer, Elizabeth E, Mei, Davide, Ballardini, Elisa, Van Haeringen, Arie, Syrbe, Steffen, Leuzzi, Vincenzo, Cioni, Giovanni, Curry, Cynthia J, Costain, Gregory, Santucci, Margherita, Chong, Karen, Mancini, Grazia M S, Clayton-Smith, Jill, Bigoni, Stefania, Scheffer, Ingrid E, Dobyns, William B, Vilsen, Bente, Guerrini, Renzo, Sanlaville, Damien, Sachdev, Rani, Andrews, Ian, Mari, Francesco, Cavalli, Anna, Barba, Carmen, De Maria, Beatrice, Garani, Giampaolo, Lemke, Johannes R, Mastrangelo, Mario, Tam, Emily, Donner, Elizabeth, Branson, Helen, Monteiro, Fabiola P, Kok, Fernando, Howell, Katherine B, Leech, Stephanie, Mefford, Heather, Muir, Alison, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Pathology, Microcephaly, Na+/K+-ATPase pump, CHILDHOOD, PHENOTYPE, 0302 clinical medicine, Na + /K + -ATPase pump, ATP1A3, Chlorocebus aethiops, Polymicrogyria, polymicrogyria, Child, NEURONS, Familial hemiplegic migraine, Brain Diseases, FAMILIAL HEMIPLEGIC MIGRAINE, ATP1A2, 3. Good health, Phenotype, Child, Preschool, COS Cells, Female, Sodium-Potassium-Exchanging ATPase, medicine.symptom, medicine.medical_specialty, Adolescent, Genotype, NA,K-ATPASE, Socio-culturale, 03 medical and health sciences, Atrophy, ALTERNATING HEMIPLEGIA, medicine, Animals, Humans, developmental and epileptic encephalopathy, SPECTRUM, Epilepsy, Cerebellar ataxia, business.industry, Alternating hemiplegia of childhood, Infant, Newborn, Infant, medicine.disease, 030104 developmental biology, DE-NOVO MUTATIONS, SUBUNIT, Mutation, Na plus /K plus -ATPase pump, Neurology (clinical), business, Brain morphogenesis, 030217 neurology & neurosurgery
Abstract

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations’ effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, ‘profound’ phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, ‘profound’ and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.

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44. Psychosocial experiences of clinicians providing care for children with severe neurological impairment.

Author

Nevin, Suzanne M., Le Marne, Fleur A., Beavis, Erin, Macintosh, Rebecca, Palmer, Elizabeth E., Sachdev, Rani, Nunn, Kenneth, and Bye, Ann

Abstract

Aim Method Results Interpretation To investigate clinicians' psychosocial experiences navigating interdisciplinary care for children with severe neurological impairment (SNI), for example children with a developmental epileptic encephalopathy; secondarily, to identify preferences for future interventions to support clinicians caring for children with SNI.We conducted a qualitative descriptive study with interdisciplinary clinicians by using a purposeful sampling recruitment strategy. Twenty‐four participants with expertise caring for children with SNI completed in‐depth, semi‐structured interviews. We transcribed the interviews, de‐identified them, and performed inductive thematic analysis.Thematic analysis elicited interrelated themes. Clinicians experienced immense professional barriers providing patient‐centred care across fragmented healthcare contexts. Physical, emotional, and psychological impacts were attributed to inadequate reflective practice training and a paucity of integrated resources to support clinicians over time. Multipronged strategies were prioritized by clinicians, incorporating psychoeducation, interdisciplinary peer mentorship, and psychological resources to build reflective practice skills for clinicians providing complex care in an advancing era of medicine.This study provides novel and in‐depth insight into clinicians' experiences navigating care for children with SNI. The results will be used to inform future integrated and multipronged co‐developed resources tailored for clinicians, on the basis of their recommendations. [ABSTRACT FROM AUTHOR]

Published
2024
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45. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.

Author

Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, Møller RS, Bellan C, Simonati A, Lesca G, Helbig KL, Palmer EE, Mei D, Ballardini E, Van Haeringen A, Syrbe S, Leuzzi V, Cioni G, Curry CJ, Costain G, Santucci M, Chong K, Mancini GMS, Clayton-Smith J, Bigoni S, Scheffer IE, Dobyns WB, Vilsen B, and Guerrini R

Subjects
Adolescent, Animals, COS Cells, Child, Child, Preschool, Chlorocebus aethiops, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Brain Diseases genetics, Epilepsy genetics, Polymicrogyria genetics, Sodium-Potassium-Exchanging ATPase genetics
Abstract

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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46. Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.

Author

Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, and Zweier C

Subjects
Adolescent, Adult, Alleles, Child, Child, Preschool, Craniofacial Abnormalities, DNA Mutational Analysis, Epilepsies, Partial genetics, Epilepsies, Partial metabolism, Epilepsy diagnosis, Female, Genetic Predisposition to Disease, Humans, Infant, Intellectual Disability diagnosis, Male, Malformations of Cortical Development genetics, Malformations of Cortical Development metabolism, Middle Aged, Pedigree, Phenotype, Syndrome, DNA Copy Number Variations, Epilepsy genetics, Intellectual Disability genetics, Membrane Proteins genetics, Mutation, Nerve Tissue Proteins genetics
Abstract

Background: Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum., Methods: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy., Results: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one., Conclusions: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Published
2016
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