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1. STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics

Author

Sinéad O’Brien, Elise Ng-Cordell, The DDD Study, Duncan E. Astle, Gaia Scerif, and Kate Baker

Subjects
STXBP1, Epilepsy, Intellectual disability, Language, Social, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Background De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. Methods To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). Results The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. Conclusions De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families.

Published
2019
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2. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau

Subjects
Science
Abstract

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.

Published
2019
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3. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride, Makanko Komara, Lihadh Al-Gazali, Aisha Al Shamsi, Elizabeth A. Fanning, Klaas J. Wierenga, Daryl A. Scott, Ziva Ben-Neriah, Vardiella Meiner, Hanoch Cassuto, Orly Elpeleg, J. Lloyd Holder, Lindsay C. Burrage, Laurie H. Seaver, Lionel Van Maldergem, Sonal Mahida, Janet S. Soul, Margaret Marlatt, Ludmila Matyakhina, Julie Vogt, June-Anne Gold, Soo-Mi Park, Vinod Varghese, Anne K. Lampe, Ajith Kumar, Melissa Lees, Muriel Holder-Espinasse, Vivienne McConnell, Birgitta Bernhard, Ed Blair, Victoria Harrison, The DDD study, Donna M. Muzny, Richard A. Gibbs, Sarah H. Elsea, Jennifer E. Posey, Weimin Bi, Seema Lalani, Fan Xia, Yaping Yang, Christine M. Eng, James R. Lupski, and Pengfei Liu

Subjects
TCF20, 22q13, Neurodevelopmental disorders, Smith–Magenis syndrome, Haploinsufficiency, Loss-of-function variants, Medicine, Genetics, QH426-470
Abstract

Abstract Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

Published
2019
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4. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau

Subjects
Science
Abstract

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Published
2018
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5. Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride, Makanko Komara, Lihadh Al-Gazali, Aisha Al Shamsi, Elizabeth A. Fanning, Klaas J. Wierenga, Daryl A. Scott, Ziva Ben-Neriah, Vardiella Meiner, Hanoch Cassuto, Orly Elpeleg, J. Lloyd Holder Jr, Lindsay C. Burrage, Laurie H. Seaver, Lionel Van Maldergem, Sonal Mahida, Janet S. Soul, Margaret Marlatt, Ludmila Matyakhina, Julie Vogt, June-Anne Gold, Soo-Mi Park, Vinod Varghese, Anne K. Lampe, Ajith Kumar, Melissa Lees, Muriel Holder-Espinasse, Vivienne McConnell, Birgitta Bernhard, Ed Blair, Victoria Harrison, The DDD study, Donna M. Muzny, Richard A. Gibbs, Sarah H. Elsea, Jennifer E. Posey, Weimin Bi, Seema Lalani, Fan Xia, Yaping Yang, Christine M. Eng, James R. Lupski, and Pengfei Liu

Subjects
Medicine, Genetics, QH426-470
Abstract

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.

Published
2019
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6. Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles

Author

Angius, Andrea, Baker, Janice A., Bedoukian, Emma, Bhambhani, Vikas, Bodamer, Olaf, O’Brien, Alan, Clayton-Smith, Jill, Crisponi, Laura, Cueto González, Anna María, the DDD study, Devriendt, Koenraad, Garrido, Elena Dominguez, Ehmke, Nadja, van Eerde, Albertien, van den Elzen, Annette P.M., Faivre, Laurence, Fisher, Laura, Flores-Daboub, Josue A., Foster, Alison, Friedman, Jennifer, Gabau, Elisabeth, Galazzi, Elena, García-Miñaúr, Sixto, Garavelli, Livia, Gardeitchik, Thatjana, Gerkes, Erica H., van Gils, Julien, Giltay, Jacques C., Garcia, Aixa Gonzalez, Heimdal, Ketil Riddervold, Horn, Denise, Houge, Gunnar, Hufnagel, Sophia B., Ilencikova, Denisa, Julia, Sophie, Kant, Sarina G., Kinning, Esther, Klee, Eric W., Kois, Chelsea, Kovačević, Maja, Lachmeijer, A.M.A. (Guus), Lanpher, Brendan, Lebrun, Marine, Leon, Eyby, Lichty, Angie Ward, Lin, Ruth, Llano-Rivas, Isabel, Lynch, Sally Ann, Maas, Saskia M., Maitz, Silvia B., McKee, Shane, Melis, Daniela, Merati, Elisabetta, Merla, Giuseppe, Newbury-Ecob, Ruth, Nizon, Mathilde, Park, Soo-Mi, Patterson, Jennifer, Petit, Florence, Peeters, Hilde, Persani, Luca, Persico, Ivana, Pes, Valentina, Pollazzon, Marzia, Potjer, Thomas, Potocki, Lorraine, Pottinger, Carrie, Prasad, Chitra, Prijoles, Eloise J., Ragge, Nicola K., Rake, Jan Peter, van Ravenswaaij-Arts, Conny M.A., Rea, Gillian, Ruivenkamp, Claudia, Rutz, Audrey, Saitta, Sulagna C., Russo, Rossana Sanchez, Santen, Gijs W.E., Schaefer, Elise, Shashi, Vandana, Schultz-Rogers, Laura, Sluga, Andrea, Sotgiu, Stefano, Steichen-Gersdorf, Elisabeth, Sullivan, Jennifer A., Sun, Yu, Suri, Mohnish, Tartaglia, Marco, Tedder, Matt, Terhal, Paulien, Tully, Ian, Verbeek, Nienke, Wenzel, Maren, White, Susan M., Xiao, Bing, Haghshenas, Sadegheh, Bout, Hidde J., Schijns, Josephine M., Levy, Michael A., Kerkhof, Jennifer, Bhai, Pratibha, McConkey, Haley, Jenkins, Zandra A., Williams, Ella M., Halliday, Benjamin J., Huisman, Sylvia A., Lauffer, Peter, de Waard, Vivian, Witteveen, Laura, Banka, Siddharth, Brady, Angela F., Hurst, Anna C.E., Kaiser, Frank J., Lacombe, Didier, Martinez-Monseny, Antonio F., Fergelot, Patricia, Monteiro, Fabíola P., Parenti, Ilaria, Santos-Simarro, Fernando, Simpson, Brittany N., Alders, Mariëlle, Robertson, Stephen P., Sadikovic, Bekim, and Menke, Leonie A.

Published
2024
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7. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Author

Bryant, Laura, Li, Dong, Cox, Samuel G, Marchione, Dylan, Joiner, Evan F, Wilson, Khadija, Janssen, Kevin, Lee, Pearl, March, Michael E, Nair, Divya, Sherr, Elliott, Fregeau, Brieana, Wierenga, Klaas J, Wadley, Alexandrea, Mancini, Grazia MS, Powell-Hamilton, Nina, van de Kamp, Jiddeke, Grebe, Theresa, Dean, John, Ross, Alison, Crawford, Heather P, Powis, Zoe, Cho, Megan T, Willing, Marcia C, Manwaring, Linda, Schot, Rachel, Nava, Caroline, Afenjar, Alexandra, Lessel, Davor, Wagner, Matias, Klopstock, Thomas, Winkelmann, Juliane, Catarino, Claudia B, Retterer, Kyle, Schuette, Jane L, Innis, Jeffrey W, Pizzino, Amy, Lüttgen, Sabine, Denecke, Jonas, Strom, Tim M, Monaghan, Kristin G, DDD Study, Yuan, Zuo-Fei, Dubbs, Holly, Bend, Renee, Lee, Jennifer A, Lyons, Michael J, Hoefele, Julia, Günthner, Roman, Reutter, Heiko, Keren, Boris, Radtke, Kelly, Sherbini, Omar, Mrokse, Cameron, Helbig, Katherine L, Odent, Sylvie, Cogne, Benjamin, Mercier, Sandra, Bezieau, Stephane, Besnard, Thomas, Kury, Sebastien, Redon, Richard, Reinson, Karit, Wojcik, Monica H, Õunap, Katrin, Ilves, Pilvi, Innes, A Micheil, Kernohan, Kristin D, Care4Rare Canada Consortium, Costain, Gregory, Meyn, M Stephen, Chitayat, David, Zackai, Elaine, Lehman, Anna, Kitson, Hilary, CAUSES Study, Martin, Martin G, Martinez-Agosto, Julian A, Undiagnosed Diseases Network, Nelson, Stan F, Palmer, Christina GS, Papp, Jeanette C, Parker, Neil H, Sinsheimer, Janet S, Vilain, Eric, Wan, Jijun, Yoon, Amanda J, Zheng, Allison, Brimble, Elise, Ferrero, Giovanni Battista, Radio, Francesca Clementina, Carli, Diana, Barresi, Sabina, Brusco, Alfredo, Tartaglia, Marco, Thomas, Jennifer Muncy, Umana, Luis, Weiss, Marjan M, Gotway, Garrett, and Stuurman, KE

Subjects
DDD Study, Care4Rare Canada Consortium, CAUSES Study, Undiagnosed Diseases Network, Cancer, Rare Diseases, Human Genome, Pediatric Research Initiative, Genetics, Biotechnology, 2.1 Biological and endogenous factors
Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020

8. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

Author

Singh, Tarjinder, Kurki, Mitja I, Curtis, David, Purcell, Shaun M, Crooks, Lucy, McRae, Jeremy, Suvisaari, Jaana, Chheda, Himanshu, Blackwood, Douglas, Breen, Gerome, Pietiläinen, Olli, Gerety, Sebastian S, Ayub, Muhammad, Blyth, Moira, Cole, Trevor, Collier, David, Coomber, Eve L, Craddock, Nick, Daly, Mark J, Danesh, John, DiForti, Marta, Foster, Alison, Freimer, Nelson B, Geschwind, Daniel, Johnstone, Mandy, Joss, Shelagh, Kirov, Georg, Körkkö, Jarmo, Kuismin, Outi, Holmans, Peter, Hultman, Christina M, Iyegbe, Conrad, Lönnqvist, Jouko, Männikkö, Minna, McCarroll, Steve A, McGuffin, Peter, McIntosh, Andrew M, McQuillin, Andrew, Moilanen, Jukka S, Moore, Carmel, Murray, Robin M, Newbury-Ecob, Ruth, Ouwehand, Willem, Paunio, Tiina, Prigmore, Elena, Rees, Elliott, Roberts, David, Sambrook, Jennifer, Sklar, Pamela, St Clair, David, Veijola, Juha, Walters, James TR, Williams, Hywel, Swedish Schizophrenia Study, INTERVAL Study, DDD Study, UK10 K Consortium, Sullivan, Patrick F, Hurles, Matthew E, O'Donovan, Michael C, Palotie, Aarno, Owen, Michael J, and Barrett, Jeffrey C

Subjects
Swedish Schizophrenia Study, INTERVAL Study, DDD Study, UK10 K Consortium, Humans, Genetic Predisposition to Disease, Histone-Lysine N-Methyltransferase, Case-Control Studies, Cohort Studies, Schizophrenia, Finland, Female, Male, Genetic Variation, Genetic Association Studies, Neurodevelopmental Disorders, Genetics, Brain Disorders, Human Genome, Serious Mental Illness, Mental Health, Clinical Research, 2.1 Biological and endogenous factors, Neurology & Neurosurgery, Neurosciences, Cognitive Sciences, Psychology
Abstract

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Published
2016

9. Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

Author

Ragge, Nicola, Isidor, Bertrand, Bitoun, Pierre, Odent, Sylvie, Giurgea, Irina, Cogné, Benjamin, Deb, Wallid, Vincent, Marie, Le Gall, Jessica, Morton, Jenny, Lim, Derek, DDD Study, Le Meur, Guylène, Zazo Seco, Celia, Zafeiropoulou, Dimitra, Bax, Dorine, Zwijnenburg, Petra, Arteche, Anara, Swafiri, Saoud Tahsin, Cleaver, Ruth, McEntagart, Meriel, Kini, Usha, Newman, William, Ayuso, Carmen, Corton, Marta, Herenger, Yvan, Jeanne, Médéric, Calvas, Patrick, and Chassaing, Nicolas

Published
2019
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10. The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Author

Piard, Juliette, Hawkes, Lara, Milh, Mathieu, Villard, Laurent, Borgatti, Renato, Romaniello, Romina, Fradin, Melanie, Capri, Yline, Héron, Delphine, Nougues, Marie-Christine, Nava, Caroline, Arsene, Oana Tarta, Shears, Debbie, Taylor, John, Pagnamenta, Alistair, Taylor, Jenny C, Sogawa, Yoshimi, Johnson, Diana, Firth, Helen, Vasudevan, Pradeep, Jones, Gabriela, Nguyen-Morel, Marie-Ange, Busa, Tiffany, Roubertie, Agathe, van den Born, Myrthe, Brischoux-Boucher, Elise, Koenig, Michel, Mignot, Cyril, DDD Study, Kini, Usha, and Philippe, Christophe

Published
2019
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11. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures

Author

Zweier, Markus, Begemann, Anaïs, McWalter, Kirsty, Cho, Megan T., Abela, Lucia, Banka, Siddharth, Behring, Bettina, Berger, Andrea, Brown, Chester W., Carneiro, Maryline, Chen, Jiani, Cooper, Gregory M., Deciphering Developmental Disorders (DDD) Study, Finnila, Candice R., Guillen Sacoto, Maria J., Henderson, Alex, Hüffmeier, Ulrike, Joset, Pascal, Kerr, Bronwyn, Lesca, Gaetan, Leszinski, Gloria S., McDermott, John Henry, Meltzer, Meira R., Monaghan, Kristin G., Mostafavi, Roya, Õunap, Katrin, Plecko, Barbara, Powis, Zöe, Purcarin, Gabriela, Reimand, Tiia, Riedhammer, Korbinian M., Schreiber, John M., Sirsi, Deepa, Wierenga, Klaas J., Wojcik, Monica H., Papuc, Sorina M., Steindl, Katharina, Sticht, Heinrich, and Rauch, Anita

Published
2019
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13. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Author

Yuan, Bo, Neira, Juanita, Pehlivan, Davut, Santiago-Sim, Teresa, Song, Xiaofei, Rosenfeld, Jill, Posey, Jennifer E., Patel, Vipulkumar, Jin, Weihong, Adam, Margaret P., Baple, Emma L., Dean, John, Fong, Chin-To, Hickey, Scott E., Hudgins, Louanne, Leon, Eyby, Madan-Khetarpal, Suneeta, Rawlins, Lettie, Rustad, Cecilie F., Stray-Pedersen, Asbjørg, Tveten, Kristian, Wenger, Olivia, Diaz, Jullianne, Jenkins, Laura, Martin, Laura, McGuire, Marianne, Pietryga, Marguerite, Ramsdell, Linda, Slattery, Leah, DDD Study, Abid, Farida, Bertuch, Alison A., Grange, Dorothy, Immken, LaDonna, Schaaf, Christian P., Van Esch, Hilde, Bi, Weimin, Cheung, Sau Wai, Breman, Amy M., Smith, Janice L., Shaw, Chad, Crosby, Andrew H., Eng, Christine, Yang, Yaping, Lupski, James R., Xiao, Rui, and Liu, Pengfei

Published
2019
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14. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

Author

Verheije, Rosalind, Kupchik, Gabriel S., Isidor, Bertrand, Kroes, Hester Y., Lynch, Sally Ann, Hawkes, Lara, Hempel, Maja, Gelb, Bruce D., Ghoumid, Jamal, D’Amours, Guylaine, Chandler, Kate, Dubourg, Christèle, Loddo, Sara, Tümer, Zeynep, Shaw-Smith, Charles, Nizon, Mathilde, Shevell, Michael, Van Hoof, Evelien, Anyane-Yeboa, Kwame, Cerbone, Gaetana, Clayton-Smith, Jill, Cogné, Benjamin, Corre, Pierre, Corveleyn, Anniek, De Borre, Marie, Hjortshøj, Tina Duelund, Fradin, Mélanie, Gewillig, Marc, Goldmuntz, Elizabeth, Hens, Greet, Lemyre, Emmanuelle, Journel, Hubert, Kini, Usha, Kortüm, Fanny, Le Caignec, Cedric, Novelli, Antonio, Odent, Sylvie, Petit, Florence, Revah-Politi, Anya, Stong, Nicholas, Strom, Tim M., van Binsbergen, Ellen, DDD study, Devriendt, Koenraad, and Breckpot, Jeroen

Published
2019
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15. Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection

Author

Zhou, Wenjun, He, Yanlin, Rehman, Atteeq U, Kong, Yan, Hong, Sungguan, Ding, Guolian, Yalamanchili, Hari Krishna, Wan, Ying-Wooi, Paul, Basil, Wang, Chuhan, Gong, Yingyun, Zhou, Wenxian, Liu, Hao, Dean, John, Scalais, Emmanuel, O’Driscoll, Mary, Morton, Jenny E. V, DDD study, Hou, Xinguo, Wu, Qi, Tong, Qingchun, Liu, Zhandong, Liu, Pengfei, Xu, Yong, and Sun, Zheng

Published
2019
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16. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author

Basilicata, M. Felicia, Bruel, Ange-Line, Semplicio, Giuseppe, Valsecchi, Claudia Isabelle Keller, Aktaş, Tuğçe, Duffourd, Yannis, Rumpf, Tobias, Morton, Jenny, Bache, Iben, Szymanski, Witold G., Gilissen, Christian, Vanakker, Olivier, Õunap, Katrin, Mittler, Gerhard, van der Burgt, Ineke, El Chehadeh, Salima, Cho, Megan T., Pfundt, Rolph, Tan, Tiong Yang, Kirchhoff, Maria, Menten, Björn, Vergult, Sarah, Lindstrom, Kristin, Reis, André, Johnson, Diana S., Fryer, Alan, McKay, Victoria, DDD Study, Fisher, Richard B., Thauvin-Robinet, Christel, Francis, David, Roscioli, Tony, Pajusalu, Sander, Radtke, Kelly, Ganesh, Jaya, Brunner, Han G., Wilson, Meredith, Faivre, Laurence, Kalscheuer, Vera M., Thevenon, Julien, and Akhtar, Asifa

Published
2018
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18. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Author

Snijders Blok, Lot, Hiatt, Susan M., Bowling, Kevin M., Prokop, Jeremy W., Engel, Krysta L., Cochran, J. Nicholas, Bebin, E. Martina, Bijlsma, Emilia K., Ruivenkamp, Claudia A. L., Terhal, Paulien, Simon, Marleen E. H., Smith, Rosemarie, Hurst, Jane A., The DDD study, McLaughlin, Heather, Person, Richard, Crunk, Amy, Wangler, Michael F., Streff, Haley, Symonds, Joseph D., Zuberi, Sameer M., Elliott, Katherine S., Sanders, Victoria R., Masunga, Abigail, Hopkin, Robert J., Dubbs, Holly A., Ortiz-Gonzalez, Xilma R., Pfundt, Rolph, Brunner, Han G., Fisher, Simon E., Kleefstra, Tjitske, and Cooper, Gregory M.

Published
2018
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19. Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

Author

Caron, Véronique, Caron, Véronique, Chassaing, Nicolas, Ragge, Nicola, Boschann, Felix, Ngu, Angelina My-Hoa, Meloche, Elisabeth, Chorfi, Sarah, Lakhani, Saquib A, Ji, Weizhen, Steiner, Laurie, Marcadier, Julien, Jansen, Philip R, van de Pol, Laura A, van Hagen, Johanna M, Russi, Alvaro Serrano, Le Guyader, Gwenaël, Nordenskjöld, Magnus, Nordgren, Ann, Anderlid, Britt-Marie, Plaisancié, Julie, Stoltenburg, Corinna, Horn, Denise, Drenckhahn, Anne, Hamdan, Fadi F, Lefebvre, Mathilde, Attie-Bitach, Tania, Forey, Peggy, Smirnov, Vasily, Ernould, Françoise, Jacquemont, Marie-Line, Grotto, Sarah, Alcantud, Alberto, Coret, Alicia, Ferrer-Avargues, Rosario, Srivastava, Siddharth, Vincent-Delorme, Catherine, Romoser, Shelby, Safina, Nicole, Saade, Dimah, Lupski, James R, Calame, Daniel G, Geneviève, David, Chatron, Nicolas, Schluth-Bolard, Caroline, Myers, Kenneth A, Dobyns, William B, Calvas, Patrick, DDD Study, Salmon, Caroline, Holt, Richard, Elmslie, Frances, Allaire, Marc, Prigozhin, Daniil M, Tremblay, André, Michaud, Jacques L, Caron, Véronique, Caron, Véronique, Chassaing, Nicolas, Ragge, Nicola, Boschann, Felix, Ngu, Angelina My-Hoa, Meloche, Elisabeth, Chorfi, Sarah, Lakhani, Saquib A, Ji, Weizhen, Steiner, Laurie, Marcadier, Julien, Jansen, Philip R, van de Pol, Laura A, van Hagen, Johanna M, Russi, Alvaro Serrano, Le Guyader, Gwenaël, Nordenskjöld, Magnus, Nordgren, Ann, Anderlid, Britt-Marie, Plaisancié, Julie, Stoltenburg, Corinna, Horn, Denise, Drenckhahn, Anne, Hamdan, Fadi F, Lefebvre, Mathilde, Attie-Bitach, Tania, Forey, Peggy, Smirnov, Vasily, Ernould, Françoise, Jacquemont, Marie-Line, Grotto, Sarah, Alcantud, Alberto, Coret, Alicia, Ferrer-Avargues, Rosario, Srivastava, Siddharth, Vincent-Delorme, Catherine, Romoser, Shelby, Safina, Nicole, Saade, Dimah, Lupski, James R, Calame, Daniel G, Geneviève, David, Chatron, Nicolas, Schluth-Bolard, Caroline, Myers, Kenneth A, Dobyns, William B, Calvas, Patrick, DDD Study, Salmon, Caroline, Holt, Richard, Elmslie, Frances, Allaire, Marc, Prigozhin, Daniil M, Tremblay, André, and Michaud, Jacques L

Abstract

PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Published
2023

21. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2019
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22. Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Vetrini, Francesco, McKee, Shane, Rosenfeld, Jill A., Suri, Mohnish, Lewis, Andrea M., Nugent, Kimberly Margaret, Roeder, Elizabeth, Littlejohn, Rebecca O., Holder, Sue, Zhu, Wenmiao, Alaimo, Joseph T., Graham, Brett, Harris, Jill M., Gibson, James B., Pastore, Matthew, McBride, Kim L., Komara, Makanko, Al-Gazali, Lihadh, Al Shamsi, Aisha, Fanning, Elizabeth A., Wierenga, Klaas J., Scott, Daryl A., Ben-Neriah, Ziva, Meiner, Vardiella, Cassuto, Hanoch, Elpeleg, Orly, Lloyd Holder Jr, J., Burrage, Lindsay C., Seaver, Laurie H., Van Maldergem, Lionel, Mahida, Sonal, Soul, Janet S., Marlatt, Margaret, Matyakhina, Ludmila, Vogt, Julie, Gold, June-Anne, Park, Soo-Mi, Varghese, Vinod, Lampe, Anne K., Kumar, Ajith, Lees, Melissa, Holder-Espinasse, Muriel, McConnell, Vivienne, Bernhard, Birgitta, Blair, Ed, Harrison, Victoria, The DDD study, Muzny, Donna M., Gibbs, Richard A., Elsea, Sarah H., Posey, Jennifer E., Bi, Weimin, Lalani, Seema, Xia, Fan, Yang, Yaping, Eng, Christine M., Lupski, James R., and Liu, Pengfei

Published
2019
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23. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Vetrini, Francesco, McKee, Shane, Rosenfeld, Jill A., Suri, Mohnish, Lewis, Andrea M., Nugent, Kimberly Margaret, Roeder, Elizabeth, Littlejohn, Rebecca O., Holder, Sue, Zhu, Wenmiao, Alaimo, Joseph T., Graham, Brett, Harris, Jill M., Gibson, James B., Pastore, Matthew, McBride, Kim L., Komara, Makanko, Al-Gazali, Lihadh, Al Shamsi, Aisha, Fanning, Elizabeth A., Wierenga, Klaas J., Scott, Daryl A., Ben-Neriah, Ziva, Meiner, Vardiella, Cassuto, Hanoch, Elpeleg, Orly, Holder, Jr, J. Lloyd, Burrage, Lindsay C., Seaver, Laurie H., Van Maldergem, Lionel, Mahida, Sonal, Soul, Janet S., Marlatt, Margaret, Matyakhina, Ludmila, Vogt, Julie, Gold, June-Anne, Park, Soo-Mi, Varghese, Vinod, Lampe, Anne K., Kumar, Ajith, Lees, Melissa, Holder-Espinasse, Muriel, McConnell, Vivienne, Bernhard, Birgitta, Blair, Ed, Harrison, Victoria, The DDD study, Muzny, Donna M., Gibbs, Richard A., Elsea, Sarah H., Posey, Jennifer E., Bi, Weimin, Lalani, Seema, Xia, Fan, Yang, Yaping, Eng, Christine M., Lupski, James R., and Liu, Pengfei

Published
2019
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24. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2019
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25. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, Christel, Nava, Caroline, Keren, Boris, Heide, Solveig, Rastetter, Agnès, Passemard, Sandrine, Chantot-Bastaraud, Sandra, Moutard, Marie-Laure, Agrawal, Pankaj B., VanNoy, Grace, Stoler, Joan M., Amor, David J., Billette de Villemeur, Thierry, Doummar, Diane, Alby, Caroline, Cormier-Daire, Valérie, Garel, Catherine, Marzin, Pauline, Scheidecker, Sophie, de Saint-Martin, Anne, Hirsch, Edouard, Korff, Christian, Bottani, Armand, Faivre, Laurence, Verloes, Alain, Orzechowski, Christine, Burglen, Lydie, Leheup, Bruno, Roume, Joelle, Andrieux, Joris, Sheth, Frenny, Datar, Chaitanya, Parker, Michael J., Pasquier, Laurent, Odent, Sylvie, Naudion, Sophie, Delrue, Marie-Ange, Le Caignec, Cédric, Vincent, Marie, Isidor, Bertrand, Renaldo, Florence, Stewart, Fiona, Toutain, Annick, Koehler, Udo, Häckl, Birgit, von Stülpnagel, Celina, Kluger, Gerhard, Møller, Rikke S., Pal, Deb, Jonson, Tord, Soller, Maria, Verbeek, Nienke E., van Haelst, Mieke M., de Kovel, Carolien, Koeleman, Bobby, Monroe, Glen, van Haaften, Gijs, Attié-Bitach, Tania, Boutaud, Lucile, Héron, Delphine, Mignot, Cyril, and DDD Study

Published
2017
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26. Expanding the phenotype of <scp> ASXL3 </scp> ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in <scp> ASXL3 </scp>

Author

Katherine Bergstrom, Nichola Foulds, Yue Si, Anne Slavotinek, John Dean, Evan Reid, Ruth Armstrong, Charlotte W. Ockeloen, Richard Fisher, Maria J. Guillen Sacoto, Dayna Morel, Fowzan S. Alkuraya, Costa Cinzia, Thomas D. Challman, Samantha A. Schrier Vergano, Francisca Milan Zamora, Naomi Meeks, John Pappas, Katheryn Grand, Abhijit Dixit, Julie S. Cohen, Ddd Study, Marjolein H. Willemsen, Serwet Demirdas, Rachel Harrison, Usha Kini, Bertrand Isidor, Patricia Blanchet, Emily Palen, Arjan Bouman, Jagdeep S. Walia, Ruth Newbury-Ecob, Rachel Rabin, Shadi Albaba, Diana Johnson, Paolo Prontera, Paula Girotto, Ange-Line Bruel, Meena Balasubramanian, Nicola K. Ragge, Schaida Schirwani, Deborah L. Renaud, Christopher Cunniff, John M. Graham, Natalie Dykzeul, Swati Naik, Valerie Slegesky, Hessa F Albassam, Maria Giovanna Tedesco, Sally Ann Lynch, Julie Vogt, Natalie Hauser, Dong Li, Deanna Alexis Carere, and Benjamin Cogné

Subjects
Genetics, Biology, medicine.disease, Phenotype, Hypotonia, Natural history, Neurodevelopmental disorder, Intellectual disability, medicine, Missense mutation, Hypertelorism, medicine.symptom, Genetics (clinical), Sequence (medicine)
Abstract

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021
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27. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2018
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28. Author Correction: Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection

Author

Zhou, Wenjun, He, Yanlin, Rehman, Atteeq U., Kong, Yan, Hong, Sungguan, Ding, Guolian, Yalamanchili, Hari Krishna, Wan, Ying-Wooi, Paul, Basil, Wang, Chuhan, Gong, Yingyun, Zhou, Wenxian, Liu, Hao, Dean, John, Scalais, Emmanuel, O’Driscoll, Mary, Morton, Jenny E. V., DDD study, Hou, Xinguo, Wu, Qi, Tong, Qingchun, Liu, Zhandong, Liu, Pengfei, Xu, Yong, and Sun, Zheng

Published
2019
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30. Evaluating variants classified as pathogenic in ClinVar in the DDD Study

Author

Ddd Study, Matthew E. Hurles, Caroline F. Wright, Panayiotis Constantinou, David R. FitzPatrick, Helen V. Firth, and Ruth Y. Eberhardt

Subjects
0301 basic medicine, Proband, reanalysis, Biology, Brief Communication, 03 medical and health sciences, 0302 clinical medicine, Data sequences, Gene Frequency, Databases, Genetic, Exome Sequencing, medicine, Humans, developmental disorders, Exome, Gene, Genetics (clinical), Likely pathogenic, Exome sequencing, Genetics, variant interpretation, medicine.disease, Developmental disorder, Minor allele frequency, 030104 developmental biology, genomic medicine, 030217 neurology & neurosurgery
Abstract

Purpose Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines. Methods We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known developmental disorder genes using exome sequence data from the Deciphering Developmental Disorders (DDD) study. Results Of these ClinVar pathogenic variants, 3.6% were identified among 13,462 DDD probands, and 1134/1352 (83.9%) had already been independently communicated to clinicians using DDD variant filtering pipelines as plausibly pathogenic. The remaining 218 variants failed consequence, inheritance, or other automated variant filters. Following clinical review of these additional variants, we were able to identify 112 variants in 107 (0.8%) DDD probands as potential diagnoses. Conclusion Lower minor allele frequency (1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.

Published
2020

32. Phenotypic and genetic spectrum of ATP6V1A encephalopathy:a disorder of lysosomal homeostasis

Author

Guerrini, R. (Renzo), Mei, D. (Davide), Kerti-Szigeti, K. (Katalin), Pepe, S. (Sara), Koenig, M. K. (Mary Kay), Von Allmen, G. (Gretchen), Cho, M. T. (Megan T), McDonald, K. (Kimberly), Baker, J. (Janice), Bhambhani, V. (Vikas), Powis, Z. (Zöe), Rodan, L. (Lance), Nabbout, R. (Rima), Barcia, G. (Giulia), Rosenfeld, J. A. (Jill A), Bacino, C. A. (Carlos A), Mignot, C. (Cyril), Power, L. H. (Lillian H), Harris, C. J. (Catharine J), Marjanovic, D. (Dragan), Møller, R. S. (Rikke S), Hammer, T. B. (Trine B), T. D. (The DDD Study), Keski Filppula, R. (Riikka), Vieira, P. (Päivi), Hildebrandt, C. (Clara), Sacharow, S. (Stephanie), U. D. (Undiagnosed Diseases Network), Maragliano, L. (Luca), Benfenati, F. (Fabio), Lachlan, K. (Katherine), Benneche, A. (Andreas), Petit, F. (Florence), de Sainte Agathe, J. M. (Jean Madeleine), Hallinan, B. (Barbara), Si, Y. (Yue), Wentzensen, I. M. (Ingrid M), Zou, F. (Fanggeng), Narayanan, V. (Vinodh), Matsumoto, N. (Naomichi), Boncristiano, A. (Alessandra), la Marca, G. (Giancarlo), Kato, M. (Mitsuhiro), Anderson, K. (Kristin), Barba, C. (Carmen), Sturiale, L. (Luisa), Garozzo, D. (Domenico), Bei, R. (Roberto), A. c. (ATP6V1A collaborators), Masuelli, L. (Laura), Conti, V. (Valerio), Novarino, G. (Gaia), and Fassio, A. (Anna)

Subjects
developmental delay, epileptic encephalopathy, lysosomal disorder, ATP6V1A, progressive brain atrophy
Abstract

Vacuolar-type H⁺-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.

Published
2022

33. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, Schaida, Albaba,Shadi, Carere, Deanna Alexis, Guillen Sacoto, Maria J., Milan Zamora, Francisca, Si Yue, Rabin, Rachel, Pappas, John, Renaud, Deborah L., Hauser, Natalie, Reid, Evan, Blanchet, Patricia, Foulds, Nichola, Dixit, Abhijit, Fisher, Richard, Armstrong, Ruth, Isidor, Bertrand, Cogne, Benjamin, Vergano, Samantha Schrier, Demirdas, Serwet, Dykzeul, Natalie, Cohen, Julie S., Grand, Katheryn, Morel, Dayna, Slavotinek, Anne, Albassam, Hessa F., Naik, Swati, Dean, John, Ragge, Nicola, Cinzia, Costa, Tedesco, Maria Giovanna, Harrison, Rachel E., Bouman, Arjan, Palen, Emily, Challman, Thomas D., Willemsen, Marjolein H., Vogt, Julie, Cunniff, Christopher, Bergstrom, Katherine, Walia, Jagdeep S., Bruel, Ange-Line, Kini, Usha, Alkuraya, Fowzan S., Slegesky, Valerie, Meeks, Naomi, Girotto, Paula, Johnson, Diana, DDD study, Newbury-Ecob, Ruth, Ockeloen, Charlotte W., Prontera, Paolo, Lynch, Sally Ann, Li Dong, Graham, John M., Jr., and Balasubramanian Meena

Abstract

Purpose. The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. Methods. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterisation of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. Results. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterise the phenotype in mildly affected individuals and discuss non-penetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioural issues, hypotonia and feeding difficulties. Distinctive features include down-slanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge and low-hanging columella. Conclusion. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

35. ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature

Author

Kushary, S.T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti-Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C.R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N.C., Mansukhani, M., McBrian, D., McEntagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C.A.L., Sacco, O., Santen, G.W.E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K.P., Woods, C.G., Yeboa, K.A., DDD Study, TUDP Consortium, Kushary, S. T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C. R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N. C., Mansukhani, M., Mcbrian, D., Mcentagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C. A. L., Sacco, O., Santen, G. W. E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K. P., Woods, C. G., and Anyane Yeboa, K.

Subjects
Male, Genotype, Mutation, Missense, genotype-phenotype correlation, Article, Congenital Abnormalities, whole exome sequencing, Minor Histocompatibility Antigens, Neuroimaging, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, business.industry, Brain, genotype–phenotype correlation, medicine.disease, SON, DNA-Binding Proteins, Phenotype, Variable dysmorphic features, Female, business, multisystemic disorder
Abstract

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype–phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.

Published
2021
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36. Dual diagnosis causing severe phenotype in a patient with Angelman syndrome

Author

Michael Parker, Ddd Study, Meena Balasubramanian, Santosh R. Mordekar, and Farah Kanani

Subjects
Male, business.industry, MEDLINE, General Medicine, medicine.disease, Bioinformatics, Phenotype, Pathology and Forensic Medicine, Text mining, Diagnosis, Dual (Psychiatry), ras GTPase-Activating Proteins, Severe phenotype, Intellectual Disability, Angelman syndrome, Pediatrics, Perinatology and Child Health, Humans, Dual diagnosis, Medicine, Angelman Syndrome, Anatomy, Child, business, Genetics (clinical)
Published
2019
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37. Correction: The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Author

Marie-Christine Nougues, Ddd Study, Yoshimi Sogawa, Juliette Piard, Christophe Philippe, John Taylor, Delphine Héron, Jenny C. Taylor, Romina Romaniello, Mathieu Milh, Pradeep Vasudevan, Oana Tarta Arsene, Usha Kini, Tiffany Busa, Debbie Shears, Mélanie Fradin, Diana Johnson, Yline Capri, Lara Hawkes, Myrthe van den Born, Gabriela E. Jones, Elise Brischoux-Boucher, Alistair T. Pagnamenta, Agathe Roubertie, Cyril Mignot, Helen V. Firth, Caroline Nava, Laurent Villard, Renato Borgatti, Marie-Ange Nguyen-Morel, and Michel Koenig

Subjects
WWOX, Genetics, Biology, Phenotype, Genetics (clinical)
Published
2019
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38. A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies

Author

Shane McKee, Christel Depienne, Diana Baralle, Ddd Study, Justine Rousseau, Philippe M. Campeau, Sophie Ehresmann, Naomichi Matsumoto, Solveig Heide, Max H. Stone, Hannah Titheradge, Alyssa Ritter, Kevin C J Nixon, Seiji Mizuno, Jamie M. Kramer, Delphine Héron, Noriko Miyake, Mohammed Sarikahya, Kosuke Izumi, Western University [London, ON, Canada], Centre Hospitalier Universitaire Sainte-Justine [Montréal, QC, Canada] (CHU Sainte-Justine), Yokohama City University (YCU), University of Southampton, Belfast City Hospital, Children’s Hospital of Philadelphia (CHOP ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Duisburg-Essen, and Birmingham Women's and Children's NHS Foundation Trust

Subjects
Male, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Medizin, Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Drosophila Proteins, Child, Genetics (clinical), Exome sequencing, Neurons, Regulation of gene expression, Genetics, 0303 health sciences, Syndrome, SWI/SNF, Hypotonia, Drosophila melanogaster, intellectual disability, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, BAFopathies, Mitosis, Context (language use), SMARCD1, Biology, Drosophila mushroom body, Article, Chromatin remodeling, 03 medical and health sciences, long-term memory, Memory, medicine, Animals, Humans, Learning, Mushroom Bodies, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, fungi, medicine.disease, neurodevelopmental disorder, Disease Models, Animal, Gene Expression Regulation, Neurodevelopmental Disorders, Mutation, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on 5 individuals with mutations in SMARCD1, presenting with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The mutations were proven to be de novo in 4 of the 5 individuals, by trio exome sequencing. Mutations in other SWI/SNF components cause Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify a NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.

Published
2019
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39. Exploring the association between SRPX2 variants and neurodevelopment: How causal is it?

Author

Vivienne McConnell, Josh Willoughby, Ddd Study, Meena Balasubramanian, and Schaida Schirwani

Subjects
Male, 0301 basic medicine, Genotype, Neurogenesis, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Speech Disorders, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Speech and language impairment, Intellectual disability, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Language disorder, Genetic Testing, SRPX2 Gene, Alleles, Genetic Association Studies, Genetic Variation, High-Throughput Nucleotide Sequencing, Infant, Membrane Proteins, FOXP2, General Medicine, medicine.disease, Phenotype, Neoplasm Proteins, Rolandic epilepsy, 030104 developmental biology, 030220 oncology & carcinogenesis, Neuroscience
Abstract

The SRPX2 gene (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642), located on Xq22.1, encodes a secreted protein that is highly expressed in neurons of cerebral cortex. SRPX2 was first implicated in neurodevelopment, learning and rolandic seizure when two patients with potentially pathogenic variants, c.980A>G (p.Asn327Ser) and c.215A>C (p.Tyr72Ser), in SRPX2 gene were identified. Subsequent experimental studies demonstrated that SRPX2 is needed for vocalization and synapse formation in mice, and that both silencing SRPX2 and injecting (p.Asn327Ser) in mouse models results in alteration in neuronal migration in cerebral cortex and epilepsy. A number of studies demonstrated that SRPX2 interacts with FOXP2 (Foxhead box protein P2), a gene responsible for speech and language disorder, and that FoxP2 controls timing and level of expression of SRPX2. Despite the supportive evidence for the role of SRPX2 in speech and language development and disorders, there are questions over its definitive association with neurodevelopmental disorders and epilepsy. In this paper, the role of SRPX2 as one in a network of many genes involved in speech and language is discussed. The goal of this paper is to examine the role of SRPX2 variants through describing two patients with potentially pathogenic variants in SRPX2, c.751G>C (p.Ala251Pro) and c.762G>T (p.Lys254Asn) presenting with language and motor delay, intellectual disability as well as congenital anomalies. We explore the contribution of SRPX2 variants to clinical phenotype in our patients and conclude that these variants at least partially explain the phenotype. Further studies are necessary to establish and confirm the association between SRPX2 and neurodevelopment particularly speech and language development.

Published
2019
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40. MAN1B-CDG: Novel variants with a distinct phenotype and review of literature

Author

Meena Balasubramanian, Diana Johnson, and Ddd Study

Subjects
Male, 0301 basic medicine, Developmental Disabilities, 030105 genetics & heredity, Bioinformatics, Recurrence risk, Craniofacial Abnormalities, 03 medical and health sciences, Congenital Disorders of Glycosylation, alpha-Mannosidase, Intellectual disability, Genetics, Humans, Medicine, Genomic medicine, Child, Genetics (clinical), Exome sequencing, chemistry.chemical_classification, business.industry, Syndrome, General Medicine, medicine.disease, Phenotype, Hypotonia, Pedigree, 030104 developmental biology, chemistry, Transferrin, Mutation, Etiology, Female, medicine.symptom, business
Abstract

Background Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases due to impaired lipid and protein glycosylation. It comprises a characteristic high frequency of intellectual disability (ID) and a wide range of clinical phenotypes. Objective To identify the underlying diagnosis in two families each with two siblings with variable level of ID through trio whole exome sequencing. Methods Both the families were recruited to the Deciphering Developmental Disorders (DDD) study to identify the aetiology for their ID. Further work-up included isoelectric focusing (IEF) of serum transferrin done to add evidence to the molecular diagnosis. Results These patients were found to have three novel variants in MAN1B1 inherited from their healthy parents. Serum transferrin IEF showed a type 2 pattern. Discussion MAN1B1 variants were initially described in association with non-syndromic ID; subsequent literature suggested that variants in MAN1B1 resulted in a CDG-type II syndrome. However, there remains a paucity of literature on detailed clinical phenotyping and it still remains a rare form of CDG. The present patients showed the phenotype previously reported in MAN1B1-CDG: a characteristic facial dysmorphism, hypotonia, truncal obesity and in some, behavioural problems. Conclusions In unexplained ID, serum transferrin should be included in the first-line screening. With advances in genomic medicine, it is important to diagnose CDG as this has implications for management and recurrence risk counselling.

Published
2019
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41. PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy

Author

Wenmiao Zhu, Haley Streff, Saadet Mercimek-Andrews, John Pappas, Vann Chau, Fan Xia, Seema R. Lalani, Rachel Rabin, Christine M. Eng, Yaping Yang, Weimin Bi, Sugi Panneerselvam, Ddd Study, Lisa Emrick, Karen J. Low, Rui Xiao, Claudia Soler-Alfonso, Jill A. Rosenfeld, Julia Wang, Anne E. Anderson, and Hongzheng Dai

Subjects
0301 basic medicine, Male, Drug Resistant Epilepsy, Adolescent, Protein subunit, Phosphatase, Gene Expression, 030105 genetics & heredity, Biology, Frameshift mutation, 03 medical and health sciences, Epilepsy, Mutant protein, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), Loss function, Sequence Analysis, RNA, Calcineurin, medicine.disease, 030104 developmental biology, Child, Preschool, Mutation, Female
Abstract

PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine-threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

Published
2021

42. Evaluating variants classified as pathogenic in ClinVar in the DDD Study

Author

Wright, Caroline F, Eberhardt, Ruth Y, Constantinou, Panayiotis, Hurles, Matthew E, FitzPatrick, David R, Firth, Helen V, DDD Study, Wright, Caroline F [0000-0003-2958-5076], and Apollo - University of Cambridge Repository

Subjects
genomic medicine, Gene Frequency, variant interpretation, Databases, Genetic, Exome Sequencing, reanalysis, Humans, developmental disorders, Exome
Abstract

PURPOSE: Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines. METHODS: We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known developmental disorder genes using exome sequence data from the Deciphering Developmental Disorders (DDD) study. RESULTS: Of these ClinVar pathogenic variants, 3.6% were identified among 13,462 DDD probands, and 1134/1352 (83.9%) had already been independently communicated to clinicians using DDD variant filtering pipelines as plausibly pathogenic. The remaining 218 variants failed consequence, inheritance, or other automated variant filters. Following clinical review of these additional variants, we were able to identify 112 variants in 107 (0.8%) DDD probands as potential diagnoses. CONCLUSION: Lower minor allele frequency (1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.

Published
2021
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43. KAT6A Syndrome

Author

Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study

Abstract

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

Published
2020
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44. Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype

Author

Sadleir, Lynette G, Mountier, Emily I, Gill, Deepak, Davis, Suzanne, Joshi, Charuta, DeVile, Catherine, Kurian, Manju A, DDD Study, Mandelstam, Simone, Wirrell, Elaine, Nickels, Katherine C, Murali, Hema R, Carvill, Gemma, Myers, Candace T, Mefford, Heather C, Scheffer, Ingrid E, Mandelstam, Simone [0000-0001-6287-0819], and Apollo - University of Cambridge Repository

Subjects
Male, Epilepsy, Developmental Disabilities, Mutation, Missense, Brain, Epilepsies, Myoclonic, Hyperkinesis, NAV1.1 Voltage-Gated Sodium Channel, Phenotype, Child, Preschool, Humans, Female, Age of Onset, Child
Abstract

OBJECTIVE: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

Published
2020
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45. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author

Thomas Besnard, Kristian Tveten, Hilary F Kitson, Jennifer A. Lee, Brieana Fregeau, Rachel Schot, Khadija Wilson, Katrin Õunap, Juliane Winkelmann, Anna Lehman, Nicola Longo, Servi J. C. Stevens, Megan T. Cho, Christina G.S. Palmer, Causes Study, Giovanni Battista Ferrero, Joy Dean, Lone W. Laulund, Grazia M.S. Mancini, Matias Wagner, Martin G. Martin, Sabine Lüttgen, Elizabeth J. Bhoj, Amanda J. Yoon, Thomas Klopstock, Janet S. Sinsheimer, Eric Vilain, Sébastien Küry, Francesca Clementina Radio, Jiddeke M. van de Kamp, Cameron Mrokse, Hakon Hakonarson, Samuel G. Cox, Jeanette C. Papp, Margot I. Van Allen, Raymond J. Louie, Constance T. R. M. Stumpel, Evan F. Joiner, Juanita Neira, Arve Vøllo, Amy Pizzino, Kelly Radtke, Celeste Simon, Michelle L. Thompson, Allison Zheng, Omar Sherbini, Marcia C. Willing, Tim M. Strom, Benjamin Garcia, Sara S. Cathey, Theresa A. Grebe, Dong Li, Marjan M. Weiss, Marco Tartaglia, Laura M Bryant, Sandra Mercier, Katherine L. Helbig, Martin Jakob Larsen, Ddd Study, Alexandrea Wadley, Alexander P.A. Stegmann, Sabina Barresi, A. Micheil Innes, Elaine H. Zackai, Gregory Costain, Davor Lessel, Molly Snyder, Heather P. Crawford, Richard Redon, Pearl Lee, Melissa Byler, Holly Dubbs, J. Gage Crump, K. E. Stuurman, Boris Keren, Stéphane Bézieau, Stan F. Nelson, Kristin G. Monaghan, Michael J. Lyons, Jeffrey W. Innis, Anna C.E. Hurst, Elizabeth A. Sellars, Samantha A. Schrier Vergano, Saadet Mercimek-Andrews, Monica H. Wojcik, Alison Ross, Heiko Reutter, Zuo-Fei Yuan, Dylan M. Marchione, Renee Bend, Diana Carli, Zöe Powis, Neil H. Parker, Jennifer Muncy Thomas, Luis A. Umaña, Adeline Vanderver, Julia Hoefele, Linda Manwaring, Christina Fagerberg, Elly Brokamp, M. Stephen Meyn, Pilvi Ilves, Xavier de la Cruz, Nina Powell-Hamilton, Caroline Nava, Garrett Gotway, Karit Reinson, Kristin D. Kernohan, Jennifer Norman, Alexandra Afenjar, Benjamin Cogné, Delphine Héron, Roman Günthner, Alfredo Brusco, John Dean, Kevin A. Janssen, Robert Roger Lebel, Divya Nair, Jijun Wan, Julian A. Martinez-Agosto, Elliott H. Sherr, Kyle Retterer, Claudia B. Catarino, Michael E. March, Natalia Padilla, Elise Brimble, Sylvie Odent, Jane L. Schuette, David Chitayat, Klaas J. Wierenga, Kirsty McWalter, Trine Prescott, Jonas Denecke, Wendy K. Chung, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), and Clinical Genetics

Subjects
metabolism [Zebrafish Proteins], RESIDUE, metabolism [Histones], GENES, Somatic cell, CODE, cancer mutation, histone, Biology, VARIANTS, medicine.disease_cause, progressive neurologic dysfunction, Histones, 03 medical and health sciences, Histone H3, 0302 clinical medicine, Germline mutation, SDG 3 - Good Health and Well-being, histone, neurodevelopmental disorder, progressive neurologic dysfunction, congenital anomalies, cancer mutation, medicine, Animals, Humans, H3-3A protein, human, metabolism [Zebrafish], TRANSCRIPTION, PHOSPHORYLATION, Gene, Zebrafish, Germ-Line Mutation, 030304 developmental biology, Genetics, genetics [Zebrafish], 0303 health sciences, Multidisciplinary, foxd3 protein, zebrafish, congenital anomalies, Forkhead Transcription Factors, Zebrafish Proteins, biology.organism_classification, genetics [Histones], neurodevelopmental disorder, H3F3B, Histone, genetics [Forkhead Transcription Factors], genetics [Neurodegenerative Diseases], biology.protein, ddc:500, Carcinogenesis, 030217 neurology & neurosurgery
Abstract

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Published
2020
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46. Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant

Author

Thabo Michael Yates, Oon-Hui Ng, Diana Johnson, Amaka C. Offiah, Ddd Study, Josh Willoughby, and Jonathan Berg

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Population, Scoliosis, Bifid rib, 030105 genetics & heredity, Consanguinity, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Microdontia, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Craniofacial, education, Skeleton, Genetics (clinical), Loss function, education.field_of_study, Tooth Abnormalities, business.industry, Homozygote, medicine.disease, Dermatology, Musculoskeletal Abnormalities, Phenotype, 030104 developmental biology, Mutation, Female, Calcium Channels, Tomography, X-Ray Computed, business, Brachycephaly
Abstract

Biallelic loss of function variants in the TMCO1 gene have been previously demonstrated to result in cerebrofaciothoracic dysplasia (CFTD; MIM #213980). The phenotype of this condition includes severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion. Only 19 molecularly confirmed patients have been previously described. Here, we present four patients with CFTD, including three brothers from a Pakistani background and an additional unrelated white Scottish patient. All share the characteristic craniofacial appearance, with severe intellectual disability and skeletal abnormalities. We further define the phenotype with comparison to the published literature, and present images to define the dysmorphic features in a previously unreported ethnic group. All of our patient series are homozygous for the same c.292_293del (p.Ser98*) TMCO1 pathogenic variant, which has been previously reported only in an isolated Amish population. Thus we provide evidence that CFTD may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1.

Published
2018
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47. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, de Brouwer, Arjan P M, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, and de Brouwer, Arjan P M

Abstract

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.

Published
2020

48. SET de novo frameshift variants associated with developmental delay and intellectual disabilities

Author

Alice Hulbert, Joanna Kennedy, Astrid Weber, Ddd Study, Miranda Splitt, Ruth Newbury-Ecob, and Ruth Richardson

Subjects
Male, 0301 basic medicine, Adolescent, Developmental Disabilities, Biology, Article, Frameshift mutation, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Histone Chaperones, Child, Frameshift Mutation, Enhancer, Set (psychology), Gene, Genetics (clinical), Exome sequencing, Variegation, medicine.disease, Phenotype, DNA-Binding Proteins, 030104 developmental biology, Female, Transcription Factors
Abstract

Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified three individuals with de novo frameshift variants in the Suppressor of Variegation, Enhancer of Zeste, and Trithorax (SET) gene. Variants in the SET gene have not previously been recognised to be associated with human developmental disorders. Here we report detailed phenotypic information and propose that SET is a new Intellectual Disability/Developmental Delay (ID/DD) gene.

Published
2018
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49. Expanding the molecular basis and phenotypic spectrum of ZDHHC9 ‐associated X‐linked intellectual disability

Author

Emma Wakeling, Schaida Schirwani, Kath Smith, Ddd Study, and Meena Balasubramanian

Subjects
Male, 0301 basic medicine, Adolescent, Genotype, X-linked intellectual disability, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Alleles, Genetic Association Studies, Genetics (clinical), Comparative Genomic Hybridization, Mutation, Point mutation, Macrocephaly, Facies, High-Throughput Nucleotide Sequencing, Infant, medicine.disease, Phenotype, Pedigree, 030104 developmental biology, Palpebral fissure, Mental Retardation, X-Linked, Female, medicine.symptom, Acyltransferases, 030217 neurology & neurosurgery
Abstract

Pathogenic variants in Zinc Finger DHHC-Type Containing 9 (ZDHHC9) gene have been identified as the cause of X-linked intellectual disability (XLID) in a small number of families. There are a total of 11 reported pathogenic variants in ZDHHC9 in the literature. The majority of reported variants are familial point mutations. There is one report of XLID associated with a de novo mutation in ZDHHC9, and one family with intragenic deletion within ZDHHC9 detected by array CGH. Although initial reports of families with ZDHHC9 pathogenic variants suggested a nonsyndromic XLID, more recent reports suggest a syndromic phenotype with facial dysmorphism. Here we report four patients with pathogenic variants in ZDHHC9, a family with two siblings and their maternal uncle who presented with XLID due to intragenic deletion of ZDHHC9 detected by array CGH and an 11-year-old boy with a de novo pathogenic missense variant in ZDHHC9, which is the first recurrent ZDHHC9 mutation. Our patients had some distinctive facial features in common, including elongated and down-slanting palpebral fissures and high hairline. Marfanoid habitus and seizures that have been previously reported in association with pathogenic variants in ZDHHC9 were absent in our cohort. Clinical information on patients with ZDHHC9-associated XLID is very scarce. New reports of families with detailed clinical description will add to the existing knowledge and help understand the condition better.

Published
2018
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50. Phenotypic spectrum associated with de novo mutations in QRICH1 gene

Author

John Dean, Ddd Study, A Ververi, Miranda Splitt, and Angela F. Brady

Subjects
0301 basic medicine, Genetics, biology, Inflammation, medicine.disease, Phenotype, QRICH1, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Speech delay, medicine, biology.protein, Autism, Creatine kinase, medicine.symptom, Gene, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing
Abstract

Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.

Published
2017
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