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51. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, primary, Cousin, Margot A., additional, Challman, Thomas D., additional, Wain, Karen E., additional, Powis, Zöe, additional, Minks, Kelly, additional, Trimouille, Aurélien, additional, Lasseaux, Eulalie, additional, Lacombre, Didier, additional, Angelini, Chloé, additional, Michaud, Vincent, additional, Van-Gils, Julien, additional, Spataro, Nino, additional, Ruiz, Anna, additional, Gabau, Elizabeth, additional, Stolerman, Elliot, additional, Washington, Camerun, additional, Louie, Raymond J., additional, Lanpher, Brendan C, additional, Kemppainen, Jennifer L., additional, Innes, A. Micheil, additional, Kooy, R. Frank, additional, Meuwissen, Marije, additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Vera, Gabriella, additional, Diderich, Karin E M, additional, Sheidley, Beth Rosen, additional, El Achkar, Christelle Moufawad, additional, Park, Meredith, additional, Hamdan, Fadi F., additional, Michaud, Jacques L., additional, Lewis, Ann J., additional, Zweier, Christiane, additional, Reis, André, additional, Wagner, Matias, additional, Weigand, Heike, additional, Journel, Hubert, additional, Keren, Boris, additional, Passemard, Sandrine, additional, Mignot, Cyril, additional, van Gassen, Koen L.I., additional, Brilstra, Eva H., additional, Itzikowitz, Gina, additional, O’Heir, Emily, additional, Allen, Jake, additional, Donald, Kirsten A., additional, Korf, Bruce R., additional, Skelton, Tammi, additional, Thompson, Michelle L, additional, Robin, Nathaniel H., additional, Rudy, Natasha, additional, Dobyns, William B., additional, Foss, Kimberly, additional, Zarate, Yuri A, additional, Bosanko, Katherine A., additional, Alembik, Yves, additional, Durand, Benjamin, additional, Mau-Them, Frédéric Tran, additional, Ranza, Emmanuelle, additional, Blanc, Xavier, additional, Antonarakis, Stylianos E., additional, McWalter, Kirsty, additional, Torti, Erin, additional, Millan, Francisca, additional, Dameron, Amy, additional, Tokita, Mari J., additional, Zimmermann, Michael T., additional, Dsouza, Nikita R., additional, Klee, Eric W., additional, Piton, Amélie, additional, and Gerard, Bénédicte, additional

Published
2020
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52. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author

Duncan, Anna R., primary, Vitobello, Antonio, additional, Collins, Stephan C., additional, Vancollie, Valerie E., additional, Lelliott, Christopher J., additional, Rodan, Lance, additional, Shi, Jiahai, additional, Seman, Ann R., additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Prontera, Paolo, additional, Guillen Sacoto, Maria J., additional, Santiago-Sim, Teresa, additional, Trimouille, Aurélien, additional, Goizet, Cyril, additional, Nizon, Mathilde, additional, Bruel, Ange-Line, additional, Philippe, Christophe, additional, Grant, Patricia E., additional, Wojcik, Monica H., additional, Stoler, Joan, additional, Genetti, Casie A., additional, van Dooren, Marieke F., additional, Maas, Saskia M., additional, Alders, Marielle, additional, Faivre, Laurence, additional, Sorlin, Arthur, additional, Yoon, Grace, additional, Yalcin, Binnaz, additional, and Agrawal, Pankaj B., additional

Published
2020
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57. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects

Author

Accogli, Andrea, Calabretta, Sara, St-Onge, Judith, Boudrahem-Addour, Nassima, Dionne-Laporte, Alexandre, Joset, Pascal, Azzarello-Burri, Silvia, Rauch, Anita, Krier, Joel, Fieg, Elizabeth, Pallais, Juan C, Undiagnosed Diseases Network, McConkie-Rosell, Allyn, McDonald, Marie, Freedman, Sharon F, Rivière, Jean-Baptiste, Lafond-Lapalme, Joël, Simpson, Brittany N, Hopkin, Robert J, Trimouille, Aurélien, Van-Gils, Julien, Begtrup, Amber, McWalter, Kirsty, Delphine, Heron, Keren, Boris, Genevieve, David, Argilli, Emanuela, Sherr, Elliott H, Severino, Mariasavina, Rouleau, Guy A, Yam, Patricia T, Charron, Frédéric, and Srour, Myriam

Subjects
Heterozygote, Eye, Medical and Health Sciences, Corpus Callosum, genital defects, Congenital, Humans, 2.1 Biological and endogenous factors, Genitalia, Aetiology, Frameshift Mutation, N-cadherin, Heart Defects, Genetics & Heredity, CDH2, Neurosciences, eye defects, Undiagnosed Diseases Network, Biological Sciences, Cadherins, Axons, cardiac defects, ACOG, Neurodevelopmental Disorders, cell-cell adhesion, intellectual disability
Abstract

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

Published
2019

58. Première description neuropathologique de deux fœtus porteurs de variants pathogènes d’EIF2B5

Author

Trimouille, Aurélien, primary, Marguet, Florent, additional, Naudion, Sophie, additional, Arveiler, Benoît, additional, Boespflug-Tanguy, Odile, additional, Sauvestre, Fanny, additional, Martin-Négrier, Marie-Laure, additional, Pelluard, Fanny, additional, Rooryck-Thambo, Caroline, additional, Lasseaux, Eulalie, additional, and Laquerriere, Annie, additional

Published
2019
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59. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects

Author

Accogli, Andrea, primary, Calabretta, Sara, additional, St-Onge, Judith, additional, Boudrahem-Addour, Nassima, additional, Dionne-Laporte, Alexandre, additional, Joset, Pascal, additional, Azzarello-Burri, Silvia, additional, Rauch, Anita, additional, Krier, Joel, additional, Fieg, Elizabeth, additional, Pallais, Juan C., additional, McConkie-Rosell, Allyn, additional, McDonald, Marie, additional, Freedman, Sharon F., additional, Rivière, Jean-Baptiste, additional, Lafond-Lapalme, Joël, additional, Simpson, Brittany N., additional, Hopkin, Robert J., additional, Trimouille, Aurélien, additional, Van-Gils, Julien, additional, Begtrup, Amber, additional, McWalter, Kirsty, additional, Delphine, Heron, additional, Keren, Boris, additional, Genevieve, David, additional, Argilli, Emanuela, additional, Sherr, Elliott H., additional, Severino, Mariasavina, additional, Rouleau, Guy A., additional, Yam, Patricia T., additional, Charron, Frédéric, additional, Srour, Myriam, additional, Acosta, Maria T., additional, Adams, David R., additional, Agrawal, Pankaj, additional, Alejandro, Mercedes E., additional, Allard, Patrick, additional, Alvey, Justin, additional, Andrews, Ashley, additional, Ashley, Euan A., additional, Azamian, Mahshid S., additional, Bacino, Carlos A., additional, Bademci, Guney, additional, Baker, Eva, additional, Balasubramanyam, Ashok, additional, Baldridge, Dustin, additional, Bale, Jim, additional, Barbouth, Deborah, additional, Batzli, Gabriel F., additional, Bayrak-Toydemir, Pinar, additional, Beggs, Alan H., additional, Bejerano, Gill, additional, Bellen, Hugo J., additional, Bernstein, Jonathan A., additional, Berry, Gerard T., additional, Bican, Anna, additional, Bick, David P., additional, Birch, Camille L., additional, Bivona, Stephanie, additional, Bohnsack, John, additional, Bonnenmann, Carsten, additional, Bonner, Devon, additional, Boone, Braden E., additional, Bostwick, Bret L., additional, Botto, Lorenzo, additional, Briere, Lauren C., additional, Brokamp, Elly, additional, Brown, Donna M., additional, Brush, Matthew, additional, Burke, Elizabeth A., additional, Burrage, Lindsay C., additional, Butte, Manish J., additional, Carey, John, additional, Carrasquillo, Olveen, additional, Chang, Ta Chen Peter, additional, Chao, Hsiao-Tuan, additional, Clark, Gary D., additional, Coakley, Terra R., additional, Cobban, Laurel A., additional, Cogan, Joy D., additional, Cole, F. Sessions, additional, Colley, Heather A., additional, Cooper, Cynthia M., additional, Cope, Heidi, additional, Craigen, William J., additional, D’Souza, Precilla, additional, Dasari, Surendra, additional, Davids, Mariska, additional, Dayal, Jyoti G., additional, Dell’Angelica, Esteban C., additional, Dhar, Shweta U., additional, Dorrani, Naghmeh, additional, Dorset, Daniel C., additional, Douine, Emilie D., additional, Draper, David D., additional, Duncan, Laura, additional, Eckstein, David J., additional, Emrick, Lisa T., additional, Eng, Christine M., additional, Esteves, Cecilia, additional, Estwick, Tyra, additional, Fernandez, Liliana, additional, Ferreira, Carlos, additional, Fieg, Elizabeth L., additional, Fisher, Paul G., additional, Fogel, Brent L., additional, Forghani, Irman, additional, Fresard, Laure, additional, Gahl, William A., additional, Godfrey, Rena A., additional, Goldman, Alica M., additional, Goldstein, David B., additional, Gourdine, Jean-Philippe F., additional, Grajewski, Alana, additional, Groden, Catherine A., additional, Gropman, Andrea L., additional, Haendel, Melissa, additional, Hamid, Rizwan, additional, Hanchard, Neil A., additional, Hayes, Nichole, additional, High, Frances, additional, Holm, Ingrid A., additional, Hom, Jason, additional, Huang, Alden, additional, Huang, Yong, additional, Isasi, Rosario, additional, Jamal, Fariha, additional, Jiang, Yong-hui, additional, Johnston, Jean M., additional, Jones, Angela L., additional, Karaviti, Lefkothea, additional, Kelley, Emily G., additional, Kiley, Dana, additional, Koeller, David M., additional, Kohane, Isaac S., additional, Kohler, Jennefer N., additional, Krakow, Deborah, additional, Krasnewich, Donna M., additional, Korrick, Susan, additional, Koziura, Mary, additional, Krier, Joel B., additional, Kyle, Jennifer E., additional, Lalani, Seema R., additional, Lam, Byron, additional, Lanpher, Brendan C., additional, Lanza, Ian R., additional, Lau, C. Christopher, additional, Lazar, Jozef, additional, LeBlanc, Kimberly, additional, Lee, Brendan H., additional, Lee, Hane, additional, Levitt, Roy, additional, Levy, Shawn E., additional, Lewis, Richard A., additional, Lincoln, Sharyn A., additional, Liu, Pengfei, additional, Liu, Xue Zhong, additional, Longo, Nicola, additional, Loo, Sandra K., additional, Loscalzo, Joseph, additional, Maas, Richard L., additional, Macnamara, Ellen F., additional, MacRae, Calum A., additional, Maduro, Valerie V., additional, Majcherska, Marta M., additional, Malicdan, May Christine V., additional, Mamounas, Laura A., additional, Manolio, Teri A., additional, Mao, Rong, additional, Markello, Thomas C., additional, Marom, Ronit, additional, Marth, Gabor, additional, Martin, Beth A., additional, Martin, Martin G., additional, Martínez-Agosto, Julian A., additional, Marwaha, Shruti, additional, May, Thomas, additional, McCauley, Jacob, additional, McCormack, Colleen E., additional, McCray, Alexa T., additional, Metz, Thomas O., additional, Might, Matthew, additional, Morava-Kozicz, Eva, additional, Moretti, Paolo M., additional, Morimoto, Marie, additional, Mulvihill, John J., additional, Murdock, David R., additional, Nath, Avi, additional, Nelson, Stan F., additional, Newberry, J. Scott, additional, Newman, John H., additional, Nicholas, Sarah K., additional, Novacic, Donna, additional, Oglesbee, Devin, additional, Orengo, James P., additional, Pace, Laura, additional, Pak, Stephen, additional, Pallais, J. Carl, additional, Palmer, Christina G.S., additional, Papp, Jeanette C., additional, Parker, Neil H., additional, Phillips, John A., additional, Posey, Jennifer E., additional, Postlethwait, John H., additional, Potocki, Lorraine, additional, Pusey, Barbara N., additional, Quinlan, Aaron, additional, Raja, Archana N., additional, Renteria, Genecee, additional, Reuter, Chloe M., additional, Rives, Lynette, additional, Robertson, Amy K., additional, Rodan, Lance H., additional, Rosenfeld, Jill A., additional, Rowley, Robb K., additional, Ruzhnikov, Maura, additional, Sacco, Ralph, additional, Sampson, Jacinda B., additional, Samson, Susan L., additional, Saporta, Mario, additional, Schaechter, Judy, additional, Schedl, Timothy, additional, Schoch, Kelly, additional, Scott, Daryl A., additional, Shakachite, Lisa, additional, Sharma, Prashant, additional, Shashi, Vandana, additional, Shields, Kathleen, additional, Shin, Jimann, additional, Signer, Rebecca, additional, Sillari, Catherine H., additional, Silverman, Edwin K., additional, Sinsheimer, Janet S., additional, Sisco, Kathy, additional, Smith, Kevin S., additional, Solnica-Krezel, Lilianna, additional, Spillmann, Rebecca C., additional, Stoler, Joan M., additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Sutton, Shirley, additional, Sweetser, David A., additional, Tabor, Holly K., additional, Tamburro, Cecelia P., additional, Tan, Queenie K.-G., additional, Tekin, Mustafa, additional, Telischi, Fred, additional, Thorson, Willa, additional, Tifft, Cynthia J., additional, Toro, Camilo, additional, Tran, Alyssa A., additional, Urv, Tiina K., additional, Velinder, Matt, additional, Viskochil, Dave, additional, Vogel, Tiphanie P., additional, Wahl, Colleen E., additional, Walley, Nicole M., additional, Walsh, Chris A., additional, Walker, Melissa, additional, Wambach, Jennifer, additional, Wan, Jijun, additional, Wang, Lee-kai, additional, Wangler, Michael F., additional, Ward, Patricia A., additional, Waters, Katrina M., additional, Webb-Robertson, Bobbie-Jo M., additional, Wegner, Daniel, additional, Westerfield, Monte, additional, Wheeler, Matthew T., additional, Wise, Anastasia L., additional, Wolfe, Lynne A., additional, Woods, Jeremy D., additional, Worthey, Elizabeth A., additional, Yamamoto, Shinya, additional, Yang, John, additional, Yoon, Amanda J., additional, Yu, Guoyun, additional, Zastrow, Diane B., additional, Zhao, Chunli, additional, and Zuchner, Stephan, additional

Published
2019
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60. PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of PUM1

Author

Bonnemason‐Carrere, Paul, primary, Morice‐Picard, Fanny, additional, Pennamen, Perrine, additional, Arveiler, Benoit, additional, Fergelot, Patricia, additional, Goizet, Cyril, additional, Hellegouarch, Mélanie, additional, Lacombe, Didier, additional, Plaisant, Claudio, additional, Raclet, Virginie, additional, Rooryck, Caroline, additional, Lasseaux, Eulalie, additional, and Trimouille, Aurélien, additional

Published
2019
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61. De novocoding variants in the AGO1gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Challman, Thomas D, Wain, Karen E, Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, Lanpher, Brendan C, Kemppainen, Jennifer L, Innes, Micheil, Kooy, Frank, Meuwissen, Marije, Goldenberg, Alice, Lecoquierre, Francois, Vera, Gabriella, Diderich, Karin E M, Sheidley, Beth, El Achkar, Christelle Moufawad, Park, Meredith, Hamdan, Fadi F, Michaud, Jacques L, Lewis, Ann J, Zweier, Christiane, Reis, André, Wagner, Matias, Weigand, Heike, Journel, Hubert, Keren, Boris, Passemard, Sandrine, Mignot, Cyril, van Gassen, Koen, Brilstra, Eva H, Itzikowitz, Gina, O'Heir, Emily, Allen, Jake, Donald, Kirsten A, Korf, Bruce Richard, Skelton, Tammi, Thompson, Michelle, Robin, Nathaniel H, Rudy, Natasha L, Dobyns, William B, Foss, Kimberly, Zarate, Yuri Alexander, Bosanko, Katherine A, Alembik, Yves, Durand, Benjamin, Tran Mau-them, Frederic, Ranza, Emmanuelle, Blanc, Xavier, Antonarakis, Stylianos E, McWalter, Kirsty, Torti, Erin, Millan, Francisca, Dameron, Amy, Tokita, Mari, Zimmermann, Michael T, Klee, Eric W, Piton, Amelie, and Gerard, Benedicte

Abstract

BackgroundHigh-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).MethodsThis study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1coding variants, occurring de novo for all those whose transmission could have been verified (26/28).ResultsA total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.ConclusionOur study establishes that de novo coding variants in AGO1are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Published
2022
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62. A MT-TL1variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author

de Boer, Elke, Ockeloen, Charlotte W., Matalonga, Leslie, Horvath, Rita, Rodenburg, Richard J., Coenen, Marieke J. H., Janssen, Mirian, Henssen, Dylan, Gilissen, Christian, Steyaert, Wouter, Paramonov, Ida, Trimouille, Aurélien, Kleefstra, Tjitske, Verloes, Alain, and Vissers, Lisenka E. L. M.

Abstract

The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n= 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1(NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

Published
2021
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65. An in-frame deletion in BICD2 associated with a non-progressive form of SMALED

Author

Trimouille, Aurélien, primary, Obre, Émilie, additional, Banneau, Guillaume, additional, Durr, Alexandra, additional, Stevanin, Giovanni, additional, Clot, Fabienne, additional, Pennamen, Perrine, additional, Perez, Jean-Thomas, additional, Bailly-Scappaticci, Clémence, additional, Rouanet, Marie, additional, Delleci, Claire, additional, Sole, Guilhem, additional, Mathis, Stéphane, additional, and Goizet, Cyril, additional

Published
2018
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66. 19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference

Author

Trimouille, Aurélien, primary, Houcinat, Nada, additional, Vuillaume, Marie-Laure, additional, Fergelot, Patricia, additional, Boucher, Cécile, additional, Toutain, Jérôme, additional, Caignec, Cédric Le, additional, Vincent, Marie, additional, Nizon, Mathilde, additional, Andrieux, Joris, additional, Vanlerberghe, Clémence, additional, Delobel, Bruno, additional, Duban, Bénédicte, additional, Mansour, Sahar, additional, Baple, Emma, additional, McKeown, Colina, additional, Poke, Gemma, additional, Robertshaw, Kate, additional, Fifield, Eve, additional, Fabretto, Antonella, additional, Pecile, Vanna, additional, Gasparini, Paolo, additional, Carrozzi, Marco, additional, Lacombe, Didier, additional, Arveiler, Benoît, additional, Rooryck, Caroline, additional, and Moutton, Sébastien, additional

Published
2017
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67. BLOC1S5pathogenic variants cause a new type of Hermansky–Pudlak syndrome

Author

Pennamen, Perrine, Le, Linh, Tingaud-Sequeira, Angèle, Fiore, Mathieu, Bauters, Anne, Van Duong Béatrice, Nguyen, Coste, Valentine, Bordet, Jean-Claude, Plaisant, Claudio, Diallo, Modibo, Michaud, Vincent, Trimouille, Aurélien, Lacombe, Didier, Lasseaux, Eulalie, Delevoye, Cédric, Picard, Fanny Morice, Delobel, Bruno, Marks, Michael S., and Arveiler, Benoit

Abstract

Hermansky–Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in ten different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in nonsyndromic or syndromic forms of albinism.

Published
2020
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68. De novo CLTCvariants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Nabais Sá, Maria J., Venselaar, Hanka, Wiel, Laurens, Trimouille, Aurélien, Lasseaux, Eulalie, Naudion, Sophie, Lacombe, Didier, Piton, Amélie, Vincent-Delorme, Catherine, Zweier, Christiane, Reis, André, Trollmann, Regina, Ruiz, Anna, Gabau, Elisabeth, Vetro, Annalisa, Guerrini, Renzo, Bakhtiari, Somayeh, Kruer, Michael C., Amor, David J., Cooper, Monica S., Bijlsma, Emilia K., Barakat, Tahsin Stefan, van Dooren, Marieke F., van Slegtenhorst, Marjon, Pfundt, Rolph, Gilissen, Christian, Willemsen, Michèl A., de Vries, Bert B. A., de Brouwer, Arjan P. M., and Koolen, David A.

Abstract

Purpose: To delineate the genotype–phenotype correlation in individuals with likely pathogenic variants in the CLTCgene. Methods: We describe 13 individuals with de novo CLTCvariants. Causality of variants was determined by using the tolerance landscape of CLTCand computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n?=?27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. Conclusions: The wide phenotypic variability associated with likely pathogenic CLTCvariants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTCvariants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Published
2020
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69. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

Author

Cavé, Hélène, primary, Caye, Aurélie, additional, Ghedira, Nehla, additional, Capri, Yline, additional, Pouvreau, Nathalie, additional, Fillot, Natacha, additional, Trimouille, Aurélien, additional, Vignal, Cédric, additional, Fenneteau, Odile, additional, Alembik, Yves, additional, Alessandri, Jean-Luc, additional, Blanchet, Patricia, additional, Boute, Odile, additional, Bouvagnet, Patrice, additional, David, Albert, additional, Dieux Coeslier, Anne, additional, Doray, Bérénice, additional, Dulac, Olivier, additional, Drouin-Garraud, Valérie, additional, Gérard, Marion, additional, Héron, Delphine, additional, Isidor, Bertrand, additional, Lacombe, Didier, additional, Lyonnet, Stanislas, additional, Perrin, Laurence, additional, Rio, Marlène, additional, Roume, Joëlle, additional, Sauvion, Sylvie, additional, Toutain, Annick, additional, Vincent-Delorme, Catherine, additional, Willems, Marjorie, additional, Baumann, Clarisse, additional, and Verloes, Alain, additional

Published
2016
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70. Deletion in 2q35 excluding the IHHgene leads to fetal severe limb anomalies and suggests a disruption of chromatin architecture

Author

Trimouille, Aurélien, Tingaud-Sequeira, Angèle, Pennamen, Perrine, André, Gwenaelle, Bouron, Julie, Boucher, Cécile, Fergelot, Patricia, Lacombe, Didier, Arveiler, Benoit, and Rooryck, Caroline

Abstract

The organization of mammalian genomes into sub-megabase sized Topologically Associated Domains (TADs) has recently been revealed by techniques derived from Chromosome Conformation Capture (3 C), such as High Chromosome Contact map (Hi-C). Disruption of this organization by structural variations can lead to ectopic interactions between enhancers and promoters, and to alteration of genes expression patterns. This mechanism has already been described as the main pathophysiological mechanism in several syndromes with congenital malformations. We describe here the case of a fetus with a severe multiple congenital anomalies syndrome, including extensive polydactyly of the four limbs. This fetus carries a de novo deletion next to the IHHgene, encompassing a TAD boundary. Such an IHHTAD boundary deletion has already been described in the Dbfmouse model, which shows a quite similar, but less severe phenotype. We hypothesize that the deletion harbored by this fetus results in the same pathophysiological mechanisms as those of the Dbfmodel. The description of this case expands the spectrum of the disruption of chromatin architecture of WNT6/IHH/EPHA4/PAX3locus, and could help to understand the mechanisms of chromatin interactions at this locus.

Published
2019
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71. Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease

Author

Masliah-Planchon, Julien, primary, Dupont, Céline, additional, Vartzelis, George, additional, Trimouille, Aurélien, additional, Eymard-Pierre, Eléonore, additional, Gay-Bellile, Mathilde, additional, Renaldo, Florence, additional, Dorboz, Imen, additional, Pagan, Cécile, additional, Quentin, Samuel, additional, Elmaleh, Monique, additional, Kotsogianni, Christina, additional, Konstantelou, Elissavet, additional, Drunat, Séverine, additional, Tabet, Anne-Claude, additional, and Boespflug-Tanguy, Odile, additional

Published
2015
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72. 19p13 microduplications encompassing NFIXare responsible for intellectual disability, short stature and small head circumference

Author

Trimouille, Aurélien, Houcinat, Nada, Vuillaume, Marie-Laure, Fergelot, Patricia, Boucher, Cécile, Toutain, Jérôme, Caignec, Cédric, Vincent, Marie, Nizon, Mathilde, Andrieux, Joris, Vanlerberghe, Clémence, Delobel, Bruno, Duban, Bénédicte, Mansour, Sahar, Baple, Emma, McKeown, Colina, Poke, Gemma, Robertshaw, Kate, Fifield, Eve, Fabretto, Antonella, Pecile, Vanna, Gasparini, Paolo, Carrozzi, Marco, Lacombe, Didier, Arveiler, Benoît, Rooryck, Caroline, and Moutton, Sébastien

Abstract

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIXgene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIXare responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-typeconcept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

Published
2018
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75. Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I

Author

Nuber, Franziska, Schimpf, Johannes, Di Rago, Jean-Paul, Tribouillard-Tanvier, Déborah, Procaccio, Vincent, Martin-Negrier, Marie-Laure, Trimouille, Aurélien, Biner, Olivier, Von Ballmoos, Christoph, and Friedrich, Thorsten

Subjects
Adult, Models, Molecular, Electron Transport Complex I, Infant, Newborn, NADH Dehydrogenase, 7. Clean energy, 3. Good health, Mitochondrial Proteins, Mutation, Operon, Benzoquinones, Escherichia coli, Humans, Plasmids
Abstract

NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients' tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.

76. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author

De Boer, Elke, Ockeloen, Charlotte W, Matalonga, Leslie, Horvath, Rita, Solve-RD SNV-Indel Working Group, Rodenburg, Richard J, Coenen, Marieke JH, Janssen, Mirian, Henssen, Dylan, Gilissen, Christian, Steyaert, Wouter, Paramonov, Ida, Solve-RD-DITF-ITHACA, Trimouille, Aurélien, Kleefstra, Tjitske, Verloes, Alain, and Vissers, Lisenka ELM

Subjects
Male, Young Adult, Epilepsy, RNA, Transfer, Leu, Intellectual Disability, Mutation, Exome Sequencing, Humans, Quadriplegia, 3. Good health
Abstract

Funder: The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257, The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

77. Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I

Author

Nuber, Franziska, Schimpf, Johannes, Di Rago, Jean-Paul, Tribouillard-Tanvier, Déborah, Procaccio, Vincent, Martin-Negrier, Marie-Laure, Trimouille, Aurélien, Biner, Olivier, Von Ballmoos, Christoph, and Friedrich, Thorsten

Subjects
631/45/607/1167, 631/45/607/1168, article, 631/45/612/1237, 7. Clean energy, 3. Good health
Abstract

Funder: Albert-Ludwigs-Universität Freiburg im Breisgau (1016), NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients’ tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.

78. Étude des topologically associated domains(TADs) en diagnostic : retour d’expérience du CHU de Bordeaux

Author

Trimouille, Aurélien, Tingaud-Sequeira, Angèle, Pennamen, Perrine, Andre, Gwenaelle, Bouron, Julie, Fergelot, Patricia, Lacombe, Didier, Arveiler, Benoit, and Rooryck-Thambo, Caroline

Abstract

L’étude de l’architecture tridimensionnelle de la chromatine par la technologie de Hi-C, dérivée de la Chromosome Conformation Capture (3C), a mis en lumière l’existence de domaines chromatiniens dénommés topologically associated domains(TADs) [1].

Published
2018
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79. De novo variants in ATP2B1 lead to neurodevelopmental delay

Author

Meer Jacob Rahimi, Nicole Urban, Meret Wegler, Heinrich Sticht, Michael Schaefer, Bernt Popp, Frank Gaunitz, Manuela Morleo, Vincenzo Nigro, Silvia Maitz, Grazia M.S. Mancini, Claudia Ruivenkamp, Eun-Kyung Suk, Tobias Bartolomaeus, Andreas Merkenschlager, Daniel Koboldt, Dennis Bartholomew, Alexander P.A. Stegmann, Margje Sinnema, Irma Duynisveld, Ramona Salvarinova, Simone Race, Bert B.A. de Vries, Aurélien Trimouille, Sophie Naudion, Daphna Marom, Uri Hamiel, Noa Henig, Florence Demurger, Nils Rahner, Enrika Bartels, J. Austin Hamm, Abbey M. Putnam, Richard Person, Rami Abou Jamra, Henry Oppermann, Rahimi, Meer Jacob, Urban, Nicole, Wegler, Meret, Sticht, Heinrich, Schaefer, Michael, Popp, Bernt, Gaunitz, Frank, Morleo, Manuela, Nigro, Vincenzo, Maitz, Silvia, Mancini, Grazia M S, Ruivenkamp, Claudia, Suk, Eun-Kyung, Bartolomaeus, Tobia, Merkenschlager, Andrea, Koboldt, Daniel, Bartholomew, Denni, Stegmann, Alexander P A, Sinnema, Margje, Duynisveld, Irma, Salvarinova, Ramona, Race, Simone, de Vries, Bert B A, Trimouille, Aurélien, Naudion, Sophie, Marom, Daphna, Hamiel, Uri, Henig, Noa, Demurger, Florence, Rahner, Nil, Bartels, Enrika, Hamm, J Austin, Putnam, Abbey M, Person, Richard, Abou Jamra, Rami, Oppermann, Henry, Clinical Genetics, MUMC+: DA KG Lab Specialisten (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output

Subjects
EXPRESSION, HOMEOSTASIS, de novo, seizure, HOUSEKEEPING FUNCTION, calcium homeostasi, Mutation, Missense, PLASMA-MEMBRANE CA2+-ATPASE, ISOFORMS, ATP2B1, Nervous System Malformations, development delay, abnormal behavior, Plasma Membrane Calcium-Transporting ATPases, CA2+, Report, BINDING, Genetics, Humans, MUTATION, Genetics (clinical), neurodevelopmental disorder, HEK293 Cells, Phenotype, Neurodevelopmental Disorders, intellectual disability
Abstract

Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder.

Published
2022

80. 19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference

Author

Vanna Pecile, Didier Lacombe, Antonella Fabretto, Cécile Boucher, Clémence Vanlerberghe, Benoit Arveiler, Emma L. Baple, Nada Houcinat, Kate Robertshaw, Patricia Fergelot, Gemma Poke, Bruno Delobel, Aurélien Trimouille, Colina McKeown, Joris Andrieux, Paolo Gasparini, Bénédicte Duban, Jérôme Toutain, Marco Carrozzi, Mathilde Nizon, Sébastien Moutton, Marie Vincent, Sahar Mansour, Cédric Le Caignec, Caroline Rooryck, Eve Fifield, Marie Laure Vuillaume, Trimouille, Aurélien, Houcinat, Nada, Vuillaume, Marie-Laure, Fergelot, Patricia, Boucher, Cécile, Toutain, Jérôme, Caignec, Cédric Le, Vincent, Marie, Nizon, Mathilde, Andrieux, Jori, Vanlerberghe, Clémence, Delobel, Bruno, Duban, Bénédicte, Mansour, Sahar, Baple, Emma, Mckeown, Colina, Poke, Gemma, Robertshaw, Kate, Fifield, Eve, Fabretto, Antonella, Pecile, Vanna, Gasparini, Paolo, Carrozzi, Marco, Lacombe, Didier, Arveiler, Benoît, Rooryck, Caroline, and Moutton, Sébastien

Subjects
Male, 0301 basic medicine, Adolescent, Genetics, Genetics (clinical), Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Intellectual Disability, Chromosome Duplication, Gene duplication, Intellectual disability, medicine, Humans, Abnormalities, Multiple, Copy-number variation, Child, biology, Sotos syndrome, Macrocephaly, Infant, Syndrome, medicine.disease, NFIX, NFI Transcription Factors, 030104 developmental biology, Child, Preschool, Chromosomal region, biology.protein, Female, medicine.symptom, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

Published
2017
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81. Scientific Business Abstracts.

Author

Cooles F, Vidal-Pedrola G, Naamane N, Pratt A, Barron-Millar B, Anderson A, Hilkens C, Casement J, Bondet V, Duffy D, Zhang F, Shukla R, Isaacs J, Little M, Payne M, Coupe N, Fairfax B, Taylor CA, Mackay S, Milotay G, Bos S, Hunter B, Mcdonald D, Merces G, Sheldon G, Pradère P, Majo J, Pulle J, Vanstapel A, Vanaudenaerde BM, Vos R, Filby AJ, Fisher AJ, Collier J, Lambton J, Suomi F, Prigent M, Guissart C, Erskine D, Rozanska A, Mccorvie T, Trimouille A, Imam A, Hobson E, Mccullagh H, Frengen E, Misceo D, Bjerre A, Smeland M, Klingenberg C, Alkuraya F, Mcfarland R, Alston C, Yue W, Legouis R, Koenig M, Lako M, Mcwilliams T, Oláhová M, Taylor R, Newman W, Harkness R, McDermott J, Metcalfe K, Khan N, Macken W, Pitceathly R, Record C, Maroofian R, Sabir A, Santra S, Urquhart J, Demain L, Byers H, Beaman G, Yue W, Taylor R, Durmusalioglu E, Atik T, Isik E, Cogulu O, Reunert J, Marquardt T, Ryba L, Buchert-Lo R, Haack T, Lassuthova P, Polavarapu K, Lochmuller H, Horvath R, Jamieson P, Reilly M, O'Keefe R, Boggan R, Ng YS, Franklin I, Alston C, Blakely E, Büchner B, Bugiardini E, Colclough K, Feeney C, Hanna M, Hattersley A, Klopstock T, Kornblum C, Mancuso M, Patel K, Pitceathly R, Pizzamiglio C, Prokisch H, Schäfer J, Schaefer A, Shepherd M, Thaele A, Thomas R, Turnbull D, Gorman G, Woodward C, McFarland R, Taylor R, Cordell H, Pickett S, Tsilifis C, Pearce M, Gennery A, Daly A, Darlay R, Zatorska M, Worthington S, Anstee Q, Cordell H, Reeves H, Nizami S, Mauricio-Muir J, McCain M, Singh R, Wordsworth J, Kadharusman M, Watson R, Masson S, McPherson S, Burt A, Tiniakos D, Littler P, Nsengimana J, Zhang S, Mann D, Jamieson D, Leslie J, Shukla R, Wilson C, Betts J, Croall I, Hoggard N, Bennett J, Naamane N, Hollingsworth KG, Pratt AG, Egail M, Feeney C, Di Leo V, Taylor RW, Dodds R, Anderson AE, Sayer AA, Isaacs JD, McCracken C, Condurache DG, Szabo L, Elghazaly H, Walter F, Meade A, Chakraverty R, Harvey N, Manisty C, Petersen S, Neubauer S, Raisi-Estabragh Z, Allen L, Taylor P, Carlsson A, Hagopian W, Hedlund E, Hill A, Jones A, Ludvigsson J, Onengut-Gumuscu S, Redondo M, Rich S, Gillespie K, Dayan C, Oram R, Resteu A, Wonders K, Schattenberg J, Straub B, Ekstedt M, Berzigotti A, Geier A, Francque S, Driessen A, Boursier J, Yki-Jarvinen H, Arola J, Aithal G, Holleboom A, Verheij J, Yunis C, Trylesinski A, Papatheodoridis G, Petta S, Romero-Gomez M, Bugianesi E, Paradis V, Ratziu V, Tiniakos D, Anstee Q, Burton J, Ciminata G, Geue C, Quinn T, Glover E, Morais M, Reynolds G, Denby L, Ali S, Lennon R, Sheerin N, Yang F, Zounemat-Kermani N, Dixey P, Adcock IM, Bloom CI, Chung KF, Govaere O, Hasoon M, Alexander L, Cockell S, Tiniakos D, Ekstedt M, Schattenberg JM, Boursier J, Bugianesi E, Ratziu V, Daly AK, and Anstee QM

Published
2024
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82. Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.

Author

Cuinat S, Quélin C, Effray C, Dubourg C, Le Bouar G, Cabaret-Dufour AS, Loget P, Proisy M, Sauvestre F, Sarreau M, Martin-Berenguer S, Beneteau C, Naudion S, Michaud V, Arveiler B, Trimouille A, Macé P, Sigaudy S, Glazunova O, Torrents J, Raymond L, Saint-Frison MH, Attié-Bitach T, Lefebvre M, Capri Y, Bourgon N, Thauvin-Robinet C, Tran Mau-Them F, Bruel AL, Vitobello A, Denommé-Pichon AS, Faivre L, Brehin AC, Goldenberg A, Patrier-Sallebert S, Perani A, Dauriat B, Bourthoumieu S, Yardin C, Marquet V, Barnique M, Fiorenza-Gasq M, Marey I, Tournadre D, Doumit R, Nugues F, Barakat TS, Bustos F, Jaillard S, Launay E, Pasquier L, and Odent S

Subjects
Humans, Male, Female, Fetus pathology, Mutation, Phenotype, Prenatal Diagnosis, Exome Sequencing, Genetic Association Studies methods, Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Abnormalities, Multiple diagnosis, Pedigree, Pregnancy, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked pathology, Genetic Diseases, X-Linked diagnosis
Abstract

Introduction: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described., Method: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases., Results: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM , outside of the two previously known mutational hotspots., Conclusion: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Published
2024
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83. Primary mitochondrial disorders and mimics: Insights from a large French cohort.

Author

Rouzier C, Pion E, Chaussenot A, Bris C, Ait-El-Mkadem Saadi S, Desquiret-Dumas V, Gueguen N, Fragaki K, Amati-Bonneau P, Barcia G, Gaignard P, Steffann J, Pennisi A, Bonnefont JP, Lebigot E, Bannwarth S, Francou B, Rucheton B, Sternberg D, Martin-Negrier ML, Trimouille A, Hardy G, Allouche S, Acquaviva-Bourdain C, Pagan C, Lebre AS, Reynier P, Cossee M, Attarian S, Paquis-Flucklinger V, and Procaccio V

Subjects
Humans, France, Child, Adult, Male, Female, Adolescent, Middle Aged, Child, Preschool, Cohort Studies, Young Adult, Infant, Exome Sequencing, Aged, Whole Genome Sequencing, DNA, Mitochondrial genetics, Diagnosis, Differential, Mitochondrial Diseases genetics, Mitochondrial Diseases diagnosis
Abstract

Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes., Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes., Results: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases., Interpretation: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2024
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84. TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.

Author

Almousa H, Lewis SA, Bakhtiari S, Nordlie SH, Pagnozzi A, Magee H, Efthymiou S, Heim JA, Cornejo P, Zaki MS, Anwar N, Maqbool S, Rahman F, Neilson DE, Vemuri A, Jin SC, Yang XR, Heidari A, van Gassen K, Trimouille A, Thauvin-Robinet C, Liu J, Bruel AL, Tomoum H, Shata MO, Hashem MO, Toosi MB, Karimiani EG, Yeşil G, Lingappa L, Baruah D, Ebrahimzadeh F, Van-Gils J, Faivre L, Zamani M, Galehdari H, Sadeghian S, Shariati G, Mohammad R, van der Smagt J, Qari A, Vincent JB, Innes AM, Dursun A, Özgül RK, Akar HT, Bilguvar K, Mignot C, Keren B, Raveli C, Burglen L, Afenjar A, Kaat LD, van Slegtenhorst M, Alkuraya F, Houlden H, Padilla-Lopez S, Maroofian R, Sacher M, and Kruer MC

Subjects
Animals, Humans, Vesicular Transport Proteins genetics, Microcephaly genetics, Intellectual Disability genetics, Dystonia, Neurodevelopmental Disorders genetics, Epilepsy genetics
Abstract

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2024
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