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

2021; Springer Science+Business Media; Volume: 141; Issue: 1 Linguagem: Inglês

10.1007/s00439-021-02383-z

1432-1203

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

Genomics and Rare Diseases

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.