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1. Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay

Author

Tan, Senwei, Zhang, Qiumeng, Zhan, Rui, Luo, Si, Han, Yaoling, Yu, Bin, Muss, Candace, Pingault, Veronique, Marlin, Sandrine, Delahaye, Andrée, Peters, Sophia, Perne, Claudia, Kreiß, Martina, Spataro, Nino, Trujillo-Quintero, Juan Pablo, Racine, Caroline, Tran-Mau-Them, Frederic, Phornphutkul, Chanika, Besterman, Aaron D., Martinez, Julian, Wang, Xiuxia, Tian, Xiaoyu, Srivastava, Siddharth, Urion, David K., Madden, Jill A., Saif, Hind Al, Morrow, Michelle M., Begtrup, Amber, Li, Xing, Jurgensmeyer, Sarah, Leahy, Peter, Zhou, Shimin, Li, Faxiang, Hu, Zhengmao, Tan, Jieqiong, Xia, Kun, and Guo, Hui

Published
2024
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2. De novo KCNA6 variants with attenuated KV1.6 channel deactivation in patients with epilepsy

Author

Salpietro, Vincenzo, Deforie, Valentina Galassi, Efthymiou, Stephanie, O'Connor, Emer, Marcé‐Grau, Anna, Maroofian, Reza, Striano, Pasquale, Zara, Federico, Morrow, Michelle M, Group, SYNAPS Study, Reich, Adi, Blevins, Amy, Sala‐Coromina, Júlia, Accogli, Andrea, Fortuna, Sara, Alesandrini, Marie, Au, PY Billie, Singhal, Nilika Shah, Cogne, Benjamin, Isidor, Bertrand, Hanna, Michael G, Macaya, Alfons, Kullmann, Dimitri M, Houlden, Henry, and Männikkö, Roope

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Pediatric, Neurodegenerative, Genetics, Biotechnology, Brain Disorders, Epilepsy, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Mutation, Neurodevelopmental Disorders, Seizures, Kv1.6 Potassium Channel, K(V)1 Shaker channel family, neurodevelopmental disorder, voltage-gated potassium channels, whole exome sequencing, SYNAPS Study Group, KV1 Shaker channel family, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveMutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.MethodsFollowing clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp.ResultsWe identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits.SignificanceThis is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Published
2023

3. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, Elisabeth, Popp, Bernt, Güse, Esther, Skinner, Cindy, van der Sluijs, Pleuntje J., Maystadt, Isabelle, Pinto, Anna Maria, Renieri, Alessandra, Bruno, Lucia Pia, Granata, Stefania, Marcelis, Carlo, Baysal, Özlem, Hartwich, Dewi, Holthöfer, Laura, Isidor, Bertrand, Cogne, Benjamin, Wieczorek, Dagmar, Capra, Valeria, Scala, Marcello, De Marco, Patrizia, Ognibene, Marzia, Jamra, Rami Abou, Platzer, Konrad, Carter, Lauren B., Kuismin, Outi, van Haeringen, Arie, Maroofian, Reza, Valenzuela, Irene, Cuscó, Ivon, Martinez-Agosto, Julian A., Rabani, Ahna M., Mefford, Heather C., Pereira, Elaine M., Close, Charlotte, Anyane-Yeboa, Kwame, Wagner, Mallory, Hannibal, Mark C., Zacher, Pia, Thiffault, Isabelle, Beunders, Gea, Umair, Muhammad, Bhola, Priya T., McGinnis, Erin, Millichap, John, van de Kamp, Jiddeke M., Prijoles, Eloise J., Dobson, Amy, Shillington, Amelle, Graham, Brett H., Garcia, Evan-Jacob, Galindo, Maureen Kelly, Ropers, Fabienne G., Nibbeling, Esther A.R., Hubbard, Gail, Karimov, Catherine, Goj, Guido, Bend, Renee, Rath, Julie, Morrow, Michelle M., Millan, Francisca, Salpietro, Vincenzo, Torella, Annalaura, Nigro, Vincenzo, Kurki, Mitja, Stevenson, Roger E., Santen, Gijs W.E., Zweier, Markus, Campeau, Philippe M., Severino, Mariasavina, Reis, André, Accogli, Andrea, and Vasileiou, Georgia

Published
2023
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4. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, Guerrot, Anne-Marie, Morrow, Michelle M., Schramm, Catherine, Zamora, Francisca Millan, Shanmugham, Anita, Liu, Shuxi, Zou, Fanggeng, Bilan, Frédéric, Le Guyader, Gwenaël, Bruel, Ange-Line, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Tran Mau-Them, Frédéric, Tessarech, Marine, Colin, Estelle, El Chehadeh, Salima, Gérard, Bénédicte, Schaefer, Elise, Cogne, Benjamin, Isidor, Bertrand, Nizon, Mathilde, Doummar, Diane, Valence, Stéphanie, Héron, Delphine, Keren, Boris, Mignot, Cyril, Coutton, Charles, Devillard, Françoise, Alaix, Anne-Sophie, Amiel, Jeanne, Colleaux, Laurence, Munnich, Arnold, Poirier, Karine, Rio, Marlène, Rondeau, Sophie, Barcia, Giulia, Callewaert, Bert, Dheedene, Annelies, Kumps, Candy, Vergult, Sarah, Menten, Björn, Chung, Wendy K., Hernan, Rebecca, Larson, Austin, Nori, Kelly, Stewart, Sarah, Wheless, James, Kresge, Christina, Pletcher, Beth A., Caumes, Roseline, Smol, Thomas, Sigaudy, Sabine, Coubes, Christine, Helm, Margaret, Smith, Rosemarie, Morrison, Jennifer, Wheeler, Patricia G., Kritzer, Amy, Jouret, Guillaume, Afenjar, Alexandra, Deleuze, Jean-François, Olaso, Robert, Boland, Anne, Poitou, Christine, Frebourg, Thierry, Houdayer, Claude, Saugier-Veber, Pascale, Nicolas, Gaël, and Lecoquierre, François

Published
2022
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5. FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder

Author

Fell, Christopher W, Hagelkruys, Astrid, Cicvaric, Ana, Horrer, Marion, Liu, Lucy, Li, Joshua Shing Shun, Stadlmann, Johannes, Polyansky, Anton A, Mereiter, Stefan, Tejada, Miguel Angel, Kokotović, Tomislav, Achuta, Venkat Swaroop, Scaramuzza, Angelica, Twyman, Kimberly A, Morrow, Michelle M, Juusola, Jane, Yan, Huifang, Wang, Jingmin, Burmeister, Margit, Choudhury, Biswa, Andersen, Thomas Levin, Wirnsberger, Gerald, Holmskov, Uffe, Perrimon, Norbert, Žagrović, Bojan, Monje, Francisco J, Moeller, Jesper Bonnet, Penninger, Josef M, and Nagy, Vanja

Published
2022
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6. De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features

Author

Mullegama, Sureni V., primary, Kiernan, Kaitlyn A., additional, Torti, Erin, additional, Pavlovsky, Ethan, additional, Tilton, Nicholas, additional, Sekula, Austin, additional, Gao, Hua, additional, Alaimo, Joseph T., additional, Engleman, Kendra, additional, Rush, Eric T., additional, Blocker, Karli, additional, Dipple, Katrina M., additional, Fettig, Veronica M., additional, Hare, Heather, additional, Glass, Ian, additional, Grange, Dorothy K., additional, Griffin, Michael, additional, Phornphutkul, Chanika, additional, Massingham, Lauren, additional, Mehta, Lakshmi, additional, Miller, Danny E., additional, Thies, Jenny, additional, Merritt, J Lawrence, additional, Muller, Eric, additional, Osmond, Matthew, additional, Sawyer, Sarah L., additional, Slaugh, Rachel, additional, Hickey, Rachel E., additional, Wolf, Barry, additional, Choudhary, Sanjeev, additional, Simonović, Miljan, additional, Zhang, Yueqing, additional, Palculict, Timothy Blake, additional, Telegrafi, Aida, additional, Carere, Deanna Alexis, additional, Wentzensen, Ingrid M., additional, Morrow, Michelle M., additional, Monaghan, Kristin G., additional, Juusola, Jane, additional, and Yang, Jun, additional

Published
2024
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8. Leveraging cancer mutation data to predict the pathogenicity of germline missense variants

Author

Haque, Bushra, primary, Cheerie, David, additional, Pan, Amy, additional, Curtis, Meredith, additional, Nalpathamkalam, Thomas, additional, Nguyen, Jimmy, additional, Salhab, Celine, additional, Thiruvahindrapura, Bhooma, additional, Zhang, Jade, additional, Couse, Madeline, additional, Hartley, Taila, additional, Morrow, Michelle M, additional, Price, E Magda, additional, Walker, Susan, additional, Malkin, David, additional, Roth, Frederick P, additional, and Costain, Gregory, additional

Published
2024
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9. CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Author

Zarate, Yuri A., Uehara, Tomoko, Abe, Kota, Oginuma, Masayuki, Harako, Sora, Ishitani, Shizuka, Lehesjoki, Anna-Elina, Bierhals, Tatjana, Kloth, Katja, Ehmke, Nadja, Horn, Denise, Holtgrewe, Manuel, Anderson, Katherine, Viskochil, David, Edgar-Zarate, Courtney L., Sacoto, Maria J. Guillen, Schnur, Rhonda E., Morrow, Michelle M., Sanchez-Valle, Amarilis, Pappas, John, Rabin, Rachel, Muona, Mikko, Anttonen, Anna-Kaisa, Platzer, Konrad, Luppe, Johannes, Gburek-Augustat, Janina, Kaname, Tadashi, Okamoto, Nobuhiko, Mizuno, Seiji, Kaido, Yusaku, Ohkuma, Yoshiaki, Hirose, Yutaka, Ishitani, Tohru, and Kosaki, Kenjiro

Published
2021
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11. Elucidating the clinical and molecular spectrum ofSMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, Elisabeth, primary, Popp, Bernt, additional, Güse, Esther, additional, Skinner, Cindy, additional, van der Sluijs, Pleuntje J., additional, Maystadt, Isabelle, additional, Pinto, Anna Maria, additional, Renieri, Alessandra, additional, Bruno, Lucia Pia, additional, Granata, Stefania, additional, Marcelis, Carlo, additional, Baysal, Özlem, additional, Hartwich, Dewi, additional, Holthöfer, Laura, additional, Isidor, Bertrand, additional, Cogne, Benjamin, additional, Wieczorek, Dagmar, additional, Capra, Valeria, additional, Scala, Marcello, additional, De Marco, Patrizia, additional, Ognibene, Marzia, additional, Jamra, Rami Abou, additional, Platzer, Konrad, additional, Carter, Lauren B., additional, Kuismin, Outi, additional, van Haeringen, Arie, additional, Maroofian, Reza, additional, Valenzuela, Irene, additional, Cuscò, Ivon, additional, Martinez-Agosto, Julian A., additional, Rabani, Ahna M., additional, Mefford, Heather C., additional, Pereira, Elaine M., additional, Close, Charlotte, additional, Anyane-Yeboa, Kwame, additional, Wagner, Mallory, additional, Hannibal, Mark C., additional, Zacher, Pia, additional, Thiffault, Isabelle, additional, Beunders, Gea, additional, Umair, Muhammad, additional, Bhola, Priya T., additional, McGinnis, Erin, additional, Millichap, John, additional, van de Kamp, Jiddeke M, additional, Prijoles, Eloise J., additional, Dobson, Amy, additional, Shillington, Amelle, additional, Graham, Brett H., additional, Garcia, Evan-Jacob, additional, Galindo, Maureen Kelly, additional, Ropers, Fabienne G., additional, Nibbeling, Esther AR, additional, Hubbard, Gail, additional, Karimov, Catherine, additional, Goj, Guido, additional, Bend, Renee, additional, Rath, Julie, additional, Morrow, Michelle M, additional, Millan, Francisca, additional, Salpietro, Vincenzo, additional, Torella, Annalaura, additional, Nigro, Vincenzo, additional, Kurki, Mitja, additional, Stevenson, Roger E, additional, Santen, Gijs W.E., additional, Zweier, Markus, additional, Campeau, Philippe M., additional, Severino, Mariasavina, additional, Reis, André, additional, Accogli, Andrea, additional, and Vasileiou, Georgia, additional

Published
2023
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12. Monoallelic loss-of-function variants in GSK3Blead to autism and developmental delay

Author

Tan, Senwei, Zhang, Qiumeng, Zhan, Rui, Luo, Si, Han, Yaoling, Yu, Bin, Muss, Candace, Pingault, Veronique, Marlin, Sandrine, Delahaye, Andrée, Peters, Sophia, Perne, Claudia, Kreiß, Martina, Spataro, Nino, Trujillo-Quintero, Juan Pablo, Racine, Caroline, Tran-Mau-Them, Frederic, Phornphutkul, Chanika, Besterman, Aaron D., Martinez, Julian, Wang, Xiuxia, Tian, Xiaoyu, Srivastava, Siddharth, Urion, David K., Madden, Jill A., Saif, Hind Al, Morrow, Michelle M., Begtrup, Amber, Li, Xing, Jurgensmeyer, Sarah, Leahy, Peter, Zhou, Shimin, Li, Faxiang, Hu, Zhengmao, Tan, Jieqiong, Xia, Kun, and Guo, Hui

Abstract

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3Bvariants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3Bis enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3bknockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3Bloss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

Published
2024
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13. TELO2 ‐related syndrome ( You‐Hoover‐Fong syndrome): Description of 14 new affected individuals and review of the literature

Author

Albokhari, Daniah, primary, Pritchard, Amanda Barone, additional, Beil, Adelyn, additional, Muss, Candace, additional, Bupp, Caleb, additional, Grange, Dorothy K., additional, Delplancq, Geoffroy, additional, Heeley, Jennifer, additional, Zuteck, Melissa, additional, Morrow, Michelle M., additional, Kuentz, Paul, additional, Palculict, Timothy Blake, additional, and Hoover‐Fong, Julie E., additional

Published
2023
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14. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders

Author

Saffari, Afshin, primary, Lau, Tracy, additional, Tajsharghi, Homa, additional, Karimiani, Ehsan Ghayoor, additional, Kariminejad, Ariana, additional, Efthymiou, Stephanie, additional, Zifarelli, Giovanni, additional, Sultan, Tipu, additional, Toosi, Mehran Beiraghi, additional, Sedighzadeh, Sahar, additional, Siu, Victoria Mok, additional, Ortigoza-Escobar, Juan Darío, additional, AlShamsi, Aisha M, additional, Ibrahim, Shahnaz, additional, Al-Sannaa, Nouriya Abbas, additional, Al-Hertani, Walla, additional, Sandra, Whalen, additional, Tarnopolsky, Mark, additional, Alavi, Shahryar, additional, Li, Chumei, additional, Day-Salvatore, Debra-Lynn, additional, Martínez-González, Maria Jesús, additional, Levandoski, Kristin M, additional, Bedoukian, Emma, additional, Madan-Khetarpal, Suneeta, additional, Idleburg, Michaela J, additional, Menezes, Minal Juliet, additional, Siddharth, Aishwarya, additional, Platzer, Konrad, additional, Oppermann, Henry, additional, Smitka, Martin, additional, Collins, Felicity, additional, Lek, Monkol, additional, Shahrooei, Mohmmad, additional, Ghavideldarestani, Maryam, additional, Herman, Isabella, additional, Rendu, John, additional, Faure, Julien, additional, Baker, Janice, additional, Bhambhani, Vikas, additional, Calderwood, Laurel, additional, Akhondian, Javad, additional, Imannezhad, Shima, additional, Mirzadeh, Hanieh Sadat, additional, Hashemi, Narges, additional, Doosti, Mohammad, additional, Safi, Mojtaba, additional, Ahangari, Najmeh, additional, Torbati, Paria Najarzadeh, additional, Abedini, Soheila, additional, Salpietro, Vincenzo, additional, Gulec, Elif Yilmaz, additional, Eshaghian, Safieh, additional, Ghazavi, Mohammadreza, additional, Pascher, Michael T, additional, Vogel, Marina, additional, Abicht, Angela, additional, Moutton, Sébastien, additional, Bruel, Ange-Line, additional, Rieubland, Claudine, additional, Gallati, Sabina, additional, Strom, Tim M, additional, Lochmüller, Hanns, additional, Mohammadi, Mohammad Hasan, additional, Alvi, Javeria Raza, additional, Zackai, Elaine H, additional, Keena, Beth A, additional, Skraban, Cara M, additional, Berger, Seth I, additional, Andrew, Erin H, additional, Rahimian, Elham, additional, Morrow, Michelle M, additional, Wentzensen, Ingrid M, additional, Millan, Francisca, additional, Henderson, Lindsay B, additional, Dafsari, Hormos Salimi, additional, Jungbluth, Heinz, additional, Gomez-Ospina, Natalia, additional, McRae, Anne, additional, Peter, Merlene, additional, Veltra, Danai, additional, Marinakis, Nikolaos M, additional, Sofocleous, Christalena, additional, Ashrafzadeh, Farah, additional, Pehlivan, Davut, additional, Lemke, Johannes R, additional, Melki, Judith, additional, Benezit, Audrey, additional, Bauer, Peter, additional, Weis, Denisa, additional, Lupski, James R, additional, Senderek, Jan, additional, Christodoulou, John, additional, Chung, Wendy K, additional, Goodchild, Rose, additional, Offiah, Amaka C, additional, Moreno-De-Luca, Andres, additional, Suri, Mohnish, additional, Ebrahimi-Fakhari, Darius, additional, Houlden, Henry, additional, and Maroofian, Reza, additional

Published
2023
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15. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Kayumi, Sayaka, primary, Pérez-Jurado, Luis A., additional, Palomares, María, additional, Rangu, Sneha, additional, Sheppard, Sarah E., additional, Chung, Wendy K., additional, Kruer, Michael C., additional, Kharbanda, Mira, additional, Amor, David J., additional, McGillivray, George, additional, Cohen, Julie S., additional, García-Miñaúr, Sixto, additional, van Eyk, Clare L., additional, Harper, Kelly, additional, Jolly, Lachlan A., additional, Webber, Dani L., additional, Barnett, Christopher P., additional, Santos-Simarro, Fernando, additional, Pacio-Míguez, Marta, additional, Pozo, Angela del, additional, Bakhtiari, Somayeh, additional, Deardorff, Matthew, additional, Dubbs, Holly A., additional, Izumi, Kosuke, additional, Grand, Katheryn, additional, Gray, Christopher, additional, Mark, Paul R., additional, Bhoj, Elizabeth J., additional, Li, Dong, additional, Ortiz-Gonzalez, Xilma R., additional, Keena, Beth, additional, Zackai, Elaine H., additional, Goldberg, Ethan M., additional, Perez de Nanclares, Guiomar, additional, Pereda, Arrate, additional, Llano-Rivas, Isabel, additional, Arroyo, Ignacio, additional, Fernández-Cuesta, María Ángeles, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, Garde, Aurore, additional, Mazel, Benoit, additional, Bruel, Ange-Line, additional, Tress, Michael L., additional, Brilstra, Eva, additional, Fine, Amena Smith, additional, Crompton, Kylie E., additional, Stegmann, Alexander P.A., additional, Sinnema, Margje, additional, Stevens, Servi C.J., additional, Nicolai, Joost, additional, Lesca, Gaetan, additional, Lion-François, Laurence, additional, Haye, Damien, additional, Chatron, Nicolas, additional, Piton, Amelie, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, Srivastava, Siddharth, additional, Bassetti, Jennifer, additional, Muss, Candace, additional, Gripp, Karen W., additional, Procopio, Rebecca A., additional, Millan, Francisca, additional, Morrow, Michelle M., additional, Assaf, Melissa, additional, Moreno-De-Luca, Andres, additional, Joss, Shelagh, additional, Hamilton, Mark J., additional, Bertoli, Marta, additional, Foulds, Nicola, additional, McKee, Shane, additional, MacLennan, Alastair H., additional, Gecz, Jozef, additional, and Corbett, Mark A., additional

Published
2022
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17. <scp>FIBCD1</scp> is an endocytic <scp>GAG</scp> receptor associated with a novel neurodevelopmental disorder

Author

Fell, Christopher W, Hagelkruys, Astrid, Cicvaric, Ana, Horrer, Marion, Liu, Lucy, Li, Joshua Shing Shun, Stadlmann, Johannes, Polyansky, Anton A, Mereiter, Stefan, Tejada, Miguel Angel, Kokotović, Tomislav, Achuta, Venkat Swaroop, Scaramuzza, Angelica, Twyman, Kimberly A, Morrow, Michelle M, Juusola, Jane, Yan, Huifang, Wang, Jingmin, Burmeister, Margit, Choudhury, Biswa, Andersen, Thomas Levin, Wirnsberger, Gerald, Holmskov, Uffe, Perrimon, Norbert, Žagrović, Bojan, Monje, Francisco J, Moeller, Jesper Bonnet, Penninger, Josef M, and Nagy, Vanja

Subjects
extracellular matrix, Receptors, Cell Surface, neurodevelopmental disorder, Endocytosis, Extracellular Matrix, Mice, glycosaminoglycans, FIBCD1, Neurodevelopmental Disorders, Animals, Humans, Molecular Medicine, genetics
Abstract

Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss-of-function by disrupting FIBCD1-CS-4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor-related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal-dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.

Published
2022
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18. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Author

Jia, Xiangbin, primary, Zhang, Shujie, additional, Tan, Senwei, additional, Du, Bing, additional, He, Mei, additional, Qin, Haisong, additional, Chen, Jia, additional, Duan, Xinyu, additional, Luo, Jingsi, additional, Chen, Fei, additional, Ouyang, Luping, additional, Wang, Jian, additional, Chen, Guodong, additional, Yu, Bin, additional, Zhang, Ge, additional, Zhang, Zimin, additional, Lyu, Yongqing, additional, Huang, Yi, additional, Jiao, Jian, additional, Chen, Jin Yun (Helen), additional, Swoboda, Kathryn J., additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Leoni, Chiara, additional, Zampino, Giuseppe, additional, Cappuccio, Gerarda, additional, Brunetti-Pierri, Nicola, additional, Gerard, Benedicte, additional, Ginglinger, Emmanuelle, additional, Richer, Julie, additional, McMillan, Hugh, additional, White-Brown, Alexandre, additional, Hoekzema, Kendra, additional, Bernier, Raphael A., additional, Kurtz-Nelson, Evangeline C., additional, Earl, Rachel K., additional, Meddens, Claartje, additional, Alders, Marielle, additional, Fuchs, Meredith, additional, Caumes, Roseline, additional, Brunelle, Perrine, additional, Smol, Thomas, additional, Kuehl, Ryan, additional, Day-Salvatore, Debra-Lynn, additional, Monaghan, Kristin G., additional, Morrow, Michelle M., additional, Eichler, Evan E., additional, Hu, Zhengmao, additional, Yuan, Ling, additional, Tan, Jieqiong, additional, Xia, Kun, additional, Shen, Yiping, additional, and Guo, Hui, additional

Published
2022
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19. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, Corbett, Mark A, Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, and Corbett, Mark A

Published
2022

21. Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

Author

Steele, Jacqueline L., primary, Morrow, Michelle M., additional, Sarnat, Harvey B., additional, Alkhunaizi, Ebba, additional, Brandt, Tracy, additional, Chitayat, David A., additional, DeFilippo, Colette P., additional, Douglas, Ganka V., additional, Dubbs, Holly A., additional, Elloumi, Houda Zghal, additional, Glassford, Megan R., additional, Hannibal, Mark C., additional, Héron, Bénédicte, additional, Kim, Linda E., additional, Marco, Elysa J., additional, Mignot, Cyril, additional, Monaghan, Kristin G., additional, Myers, Kenneth A., additional, Parikh, Sumit, additional, Quinonez, Shane C., additional, Rajabi, Farrah, additional, Shankar, Suma P., additional, Shinawi, Marwan S., additional, van de Kamp, Jiddeke J.P., additional, Veerapandiyan, Aravindhan, additional, Waldman, Amy T., additional, and Graf, William D., additional

Published
2022
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22. De novo KCNA6 variants with attenuated KV1.6 channel deactivation in patients with epilepsy.

Author

Salpietro, Vincenzo, Galassi Deforie, Valentina, Efthymiou, Stephanie, O'Connor, Emer, Marcé‐Grau, Anna, Maroofian, Reza, Striano, Pasquale, Zara, Federico, Morrow, Michelle M., Reich, Adi, Blevins, Amy, Sala‐Coromina, Júlia, Accogli, Andrea, Fortuna, Sara, Alesandrini, Marie, Au, P. Y. Billie, Singhal, Nilika Shah, Cogne, Benjamin, Isidor, Bertrand, and Hanna, Michael G.

Subjects
PEOPLE with epilepsy, ION channels, SEIZURES (Medicine), EPILEPSY, NEUROLOGICAL disorders, NEURAL development
Abstract

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. Methods: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two‐electrode voltage clamp. Results: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore‐lining S6 α‐helix of KV1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co‐expressed with wild‐type KV1.6 or KV1.1 subunits. Significance: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain‐of‐function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies. [ABSTRACT FROM AUTHOR]

Published
2023
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23. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, primary, Guerrot, Anne-Marie, additional, Morrow, Michelle M., additional, Schramm, Catherine, additional, Zamora, Francisca Millan, additional, Shanmugham, Anita, additional, Liu, Shuxi, additional, Zou, Fanggeng, additional, Bilan, Frédéric, additional, Le Guyader, Gwenaël, additional, Bruel, Ange-Line, additional, Denommé-Pichon, Anne-Sophie, additional, Faivre, Laurence, additional, Tran Mau-Them, Frédéric, additional, Tessarech, Marine, additional, Colin, Estelle, additional, El Chehadeh, Salima, additional, Gérard, Bénédicte, additional, Schaefer, Elise, additional, Cogne, Benjamin, additional, Isidor, Bertrand, additional, Nizon, Mathilde, additional, Doummar, Diane, additional, Valence, Stéphanie, additional, Héron, Delphine, additional, Keren, Boris, additional, Mignot, Cyril, additional, Coutton, Charles, additional, Devillard, Françoise, additional, Alaix, Anne-Sophie, additional, Amiel, Jeanne, additional, Colleaux, Laurence, additional, Munnich, Arnold, additional, Poirier, Karine, additional, Rio, Marlène, additional, Rondeau, Sophie, additional, Barcia, Giulia, additional, Callewaert, Bert, additional, Dheedene, Annelies, additional, Kumps, Candy, additional, Vergult, Sarah, additional, Menten, Björn, additional, Chung, Wendy K., additional, Hernan, Rebecca, additional, Larson, Austin, additional, Nori, Kelly, additional, Stewart, Sarah, additional, Wheless, James, additional, Kresge, Christina, additional, Pletcher, Beth A., additional, Caumes, Roseline, additional, Smol, Thomas, additional, Sigaudy, Sabine, additional, Coubes, Christine, additional, Helm, Margaret, additional, Smith, Rosemarie, additional, Morrison, Jennifer, additional, Wheeler, Patricia G., additional, Kritzer, Amy, additional, Jouret, Guillaume, additional, Afenjar, Alexandra, additional, Deleuze, Jean-François, additional, Olaso, Robert, additional, Boland, Anne, additional, Poitou, Christine, additional, Frebourg, Thierry, additional, Houdayer, Claude, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, and Lecoquierre, François, additional

Published
2021
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24. FIBCD1 is a Conserved Receptor for Chondroitin Sulphate Proteoglycans of the Brain Extracellular Matrix and a Candidate Gene for a Complex Neurodevelopmental Disorder

Author

Fell, Christopher W, primary, Hagelkruys, Astrid, additional, Cicvaric, Ana, additional, Horrer, Marion, additional, Liu, Lucy, additional, Li, Joshua Shing Shun, additional, Stadlmann, Johannes, additional, Polyansky, Anton A, additional, Mereiter, Stefan, additional, Tejada, Miguel Angel, additional, Kokotović, Tomislav, additional, Scaramuzza, Angelica, additional, Twyman, Kimberly A, additional, Morrow, Michelle M, additional, Juusola, Jane, additional, Yan, Huifang, additional, Wang, Jingmin, additional, Burmeister, Margit, additional, Andersen, Thomas Levin, additional, Wirnsberger, Gerald, additional, Holmskov, Uffe, additional, Perrimon, Norbert, additional, Zagrović, Bojan, additional, Monje, Francisco J, additional, Moeller, Jesper Bonnet, additional, Penninger, Josef M, additional, and Nagy, Vanja, additional

Published
2021
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25. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder

Author

Sleyp, Yoeri, Valenzuela, Irene, Accogli, Andrea, Ballon, Katleen, Ben-Zeev, Bruria, Berkovic, Samuel F., Broly, Martin, Callaerts, Patrick, Caylor, Raymond C., Charles, Perrine, Chatron, Nicolas, Cohen, Lior, Coppola, Antonietta, Cordeiro, Dawn, Cuccurullo, Claudia, Cuscó, Ivon, diMonda, Janette, Duran-Romaña, Ramon, Ekhilevitch, Nina, Fernández-Alvarez, Paula, Gordon, Christopher T., Isidor, Bertrand, Keren, Boris, Lesca, Gaetan, Maljaars, Jarymke, Mercimek-Andrews, Saadet, Morrow, Michelle M., Muir, Alison M., Rousseau, Frederic, Salpietro, Vincenzo, Scheffer, Ingrid E., Schnur, Rhonda E., Schymkowitz, Joost, Souche, Erika, Steyaert, Jean, Stolerman, Elliot S., Vengoechea, Jaime, Ville, Dorothée, Washington, Camerun, Weiss, Karin, Zaid, Rinat, Sadleir, Lynette G., Mefford, Heather C., and Peeters, Hilde

Abstract

KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.

Published
2022
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26. Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Author

Motta, Marialetizia, primary, Pannone, Luca, additional, Pantaleoni, Francesca, additional, Bocchinfuso, Gianfranco, additional, Radio, Francesca Clementina, additional, Cecchetti, Serena, additional, Ciolfi, Andrea, additional, Di Rocco, Martina, additional, Elting, Mariet W., additional, Brilstra, Eva H., additional, Boni, Stefania, additional, Mazzanti, Laura, additional, Tamburrino, Federica, additional, Walsh, Larry, additional, Payne, Katelyn, additional, Fernández-Jaén, Alberto, additional, Ganapathi, Mythily, additional, Chung, Wendy K., additional, Grange, Dorothy K., additional, Dave-Wala, Ashita, additional, Reshmi, Shalini C., additional, Bartholomew, Dennis W., additional, Mouhlas, Danielle, additional, Carpentieri, Giovanna, additional, Bruselles, Alessandro, additional, Pizzi, Simone, additional, Bellacchio, Emanuele, additional, Piceci-Sparascio, Francesca, additional, Lißewski, Christina, additional, Brinkmann, Julia, additional, Waclaw, Ronald R., additional, Waisfisz, Quinten, additional, van Gassen, Koen, additional, Wentzensen, Ingrid M., additional, Morrow, Michelle M., additional, Álvarez, Sara, additional, Martínez-García, Mónica, additional, De Luca, Alessandro, additional, Memo, Luigi, additional, Zampino, Giuseppe, additional, Rossi, Cesare, additional, Seri, Marco, additional, Gelb, Bruce D., additional, Zenker, Martin, additional, Dallapiccola, Bruno, additional, Stella, Lorenzo, additional, Prada, Carlos E., additional, Martinelli, Simone, additional, Flex, Elisabetta, additional, and Tartaglia, Marco, additional

Published
2020
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27. Novel NUDT2 variant causes intellectual disability and polyneuropathy.

Author

Diaz, Frank, Khosa, Shaweta, Niyazov, Dmitriy, Lee, Hane, Person, Richard, Morrow, Michelle M., Signer, Rebecca, Dorrani, Naghmeh, Zheng, Allison, Herzog, Matthew, Freundlich, Robert, Birath, J. Brandon, Cervantes‐Manzo, Yurivia, Martinez‐Agosto, Julian A., Palmer, Christina, Nelson, Stanley F., Fogel, Brent L., and Mishra, Shri K.

Subjects
INTELLECTUAL disabilities, POLYNEUROPATHIES, DEVELOPMENTAL delay, LEG, ETIOLOGY of diseases, NUCLEOTIDE sequencing
Abstract

Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features. [ABSTRACT FROM AUTHOR]

Published
2020
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29. New Roles for the External Globus Pallidus in Basal Ganglia Circuits and Behavior.

Author

Gittis, Aryn H., Berke, Joshua D., Bevan, Mark D., Chan, C. Savio, Mallet, Nicolas, Morrow, Michelle M., and Schmidt, Robert

Subjects
GLOBUS pallidus, ELECTROPHYSIOLOGY, LABORATORY mice, BASAL ganglia, NEURAL circuitry, DEVELOPMENTAL psychobiology, CELL populations
Abstract

The development of methodology to identify specific cell populations and circuits within the basal ganglia is rapidly transforming our ability to understand the function of this complex circuit. This mini-symposium highlights recent advances in delineating the organization and function of neural circuits in the external segment of the globus pallidus (GPe). Although long considered a homogeneous structure in the motor-suppressing "indirect-pathway," the GPe consists of a number of distinct cell types and anatomical subdomains that contribute differentially to both motor and nonmotor features of behavior. Here, we integrate recent studies using techniques, such as viral tracing, transgenic mice, electrophysiology, and behavioral approaches, to create a revised framework for understanding how the GPe relates to behavior in both health and disease. [ABSTRACT FROM AUTHOR]

Published
2014
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30. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Author

Xiangbin Jia, Shujie Zhang, Senwei Tan, Bing Du, Mei He, Haisong Qin, Jia Chen, Xinyu Duan, Jingsi Luo, Fei Chen, Luping Ouyang, Jian Wang, Guodong Chen, Bin Yu, Ge Zhang, Zimin Zhang, Yongqing Lyu, Yi Huang, Jian Jiao, Jin Yun (Helen) Chen, Kathryn J. Swoboda, Emanuele Agolini, Antonio Novelli, Chiara Leoni, Giuseppe Zampino, Gerarda Cappuccio, Nicola Brunetti-Pierri, Benedicte Gerard, Emmanuelle Ginglinger, Julie Richer, Hugh McMillan, Alexandre White-Brown, Kendra Hoekzema, Raphael A. Bernier, Evangeline C. Kurtz-Nelson, Rachel K. Earl, Claartje Meddens, Marielle Alders, Meredith Fuchs, Roseline Caumes, Perrine Brunelle, Thomas Smol, Ryan Kuehl, Debra-Lynn Day-Salvatore, Kristin G. Monaghan, Michelle M. Morrow, Evan E. Eichler, Zhengmao Hu, Ling Yuan, Jieqiong Tan, Kun Xia, Yiping Shen, Hui Guo, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Jia, Xiangbin, Zhang, Shujie, Tan, Senwei, Du, Bing, He, Mei, Qin, Haisong, Chen, Jia, Duan, Xinyu, Luo, Jingsi, Chen, Fei, Ouyang, Luping, Wang, Jian, Chen, Guodong, Yu, Bin, Zhang, Ge, Zhang, Zimin, Lyu, Yongqing, Huang, Yi, Jiao, Jian, Chen, Jin Yun Helen, Swoboda, Kathryn J, Agolini, Emanuele, Novelli, Antonio, Leoni, Chiara, Zampino, Giuseppe, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Gerard, Benedicte, Ginglinger, Emmanuelle, Richer, Julie, Mcmillan, Hugh, White-Brown, Alexandre, Hoekzema, Kendra, Bernier, Raphael A, Kurtz-Nelson, Evangeline C, Earl, Rachel K, Meddens, Claartje, Alders, Marielle, Fuchs, Meredith, Caumes, Roseline, Brunelle, Perrine, Smol, Thoma, Kuehl, Ryan, Day-Salvatore, Debra-Lynn, Monaghan, Kristin G, Morrow, Michelle M, Eichler, Evan E, Hu, Zhengmao, Yuan, Ling, Tan, Jieqiong, Xia, Kun, Shen, Yiping, and Guo, Hui

Subjects
Multidisciplinary, Animal, DNA Helicases, RNA Helicase, DNA Helicase, Stress Granule, Stress Granules, Mice, RNA Recognition Motif Proteins, Neurodevelopmental Disorders, RNA Recognition Motif Protein, Animals, Poly-ADP-Ribose Binding Proteins, RNA Helicases, Poly-ADP-Ribose Binding Protein
Abstract

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L , which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes ( G3BP1 , G3BP2 , and UBAP2L ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1 , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

Published
2022

31. Biallelic ZBTB11 Variants: A Neurodevelopmental Condition with Progressive Complex Movement Disorders.

Author

Ortigoza-Escobar JD, Zamani M, Dorison N, Sadeghian S, Azizimalamiri R, Alvi JR, Sultan T, Galehdari H, Shariati G, Saberi A, Leeuwen L, Zifarelli G, Bauer P, d'Hardemare V, Doummar D, Roze E, Travaglini L, Nicita F, Ojea Ponce N, Zahraei SM, Alabdi L, Tamim A, Hashem MO, Ababneh F, Morrow MM, Curry C, Tam A, Ruedy J, Bhambhani V, Veith R, Strømme P, Efthymiou S, Alkuraya FS, Moreno-De-Luca A, Burglen L, Houlden H, and Maroofian R

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Young Adult, Neurodevelopmental Disorders genetics, Phenotype, Repressor Proteins genetics, Movement Disorders genetics
Abstract

Background: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69)., Objective: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities., Methods: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization., Results: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants., Conclusions: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Published
2024
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32. De novo KCNA6 variants with attenuated K V 1.6 channel deactivation in patients with epilepsy.

Author

Salpietro V, Galassi Deforie V, Efthymiou S, O'Connor E, Marcé-Grau A, Maroofian R, Striano P, Zara F, Morrow MM, Reich A, Blevins A, Sala-Coromina J, Accogli A, Fortuna S, Alesandrini M, Au PYB, Singhal NS, Cogne B, Isidor B, Hanna MG, Macaya A, Kullmann DM, Houlden H, and Männikkö R

Subjects
Humans, Mutation genetics, Seizures genetics, Kv1.6 Potassium Channel genetics, Epilepsy genetics, Neurodevelopmental Disorders
Abstract

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies., Methods: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp., Results: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of K V 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type K V 1.6 or K V 1.1 subunits., Significance: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2023
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33. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

Author

Sleyp Y, Valenzuela I, Accogli A, Ballon K, Ben-Zeev B, Berkovic SF, Broly M, Callaerts P, Caylor RC, Charles P, Chatron N, Cohen L, Coppola A, Cordeiro D, Cuccurullo C, Cuscó I, Janette diMonda, Duran-Romaña R, Ekhilevitch N, Fernández-Alvarez P, Gordon CT, Isidor B, Keren B, Lesca G, Maljaars J, Mercimek-Andrews S, Morrow MM, Muir AM, Rousseau F, Salpietro V, Scheffer IE, Schnur RE, Schymkowitz J, Souche E, Steyaert J, Stolerman ES, Vengoechea J, Ville D, Washington C, Weiss K, Zaid R, Sadleir LG, Mefford HC, and Peeters H

Subjects
Child, Humans, Adaptor Proteins, Signal Transducing genetics, Developmental Disabilities, Mutation, Missense genetics, Ubiquitin-Protein Ligases genetics, Autism Spectrum Disorder genetics, Epilepsy genetics, Intellectual Disability genetics, Seizures, Febrile
Abstract

Purpose: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20., Methods: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed., Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM&#95;014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface., Conclusion: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity., Competing Interests: Conflict of Interest M.M.M. and R.E.S. are employees of GeneDx, Inc. All other authors declare no conflict interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Published
2022
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