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

Juliette Coursimault, Department of Genetics and Reference Center for Developmental Disorders, Normandie Univ, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, F-76000, Rouen, France.
Anne-Marie Guerrot, Department of Genetics and Reference Center for Developmental Disorders, Normandie Univ, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, F-76000, Rouen, France.
Michelle M. Morrow, GeneDx, Gaithersburg, 20877 MD, USA.
Catherine Schramm, Department of Genetics and Reference Center for Developmental Disorders, Normandie Univ, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, F-76000, Rouen, France.
Francisca Millan Zamora, GeneDx, Gaithersburg, 20877 MD, USA.
Anita Shanmugham, GeneDx, Gaithersburg, 20877 MD, USA.
Shuxi Liu, GeneDx, Gaithersburg, 20877 MD, USA.
Fanggeng Zou, GeneDx, Gaithersburg, 20877 MD, USA.
Frédéric Bilan, Service de Génétique, Centre Hospitalier Universitaire de Poitiers, BP577, 86021, Poitiers, France.
Gwenaël Le Guyader, Service de Génétique, Centre Hospitalier Universitaire de Poitiers, BP577, 86021, Poitiers, France.
Ange-Line Bruel, UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
Anne-Sophie Denommé-Pichon, UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
Laurence Faivre, UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
Frédéric Tran Mau-Them, UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
Marine Tessarech, Service de Génétique Médicale, CHU d'Angers, Angers, France.
Estelle Colin, Service de Génétique Médicale, CHU d'Angers, Angers, France.
Salima El Chehadeh, Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
Bénédicte Gérard, Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
Elise Schaefer, Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
Benjamin Cogne, Service de Génétique Médicale, CHU Nantes, Nantes, France.
Bertrand Isidor, Service de Génétique Médicale, CHU Nantes, Nantes, France.
Mathilde Nizon, Service de Génétique Médicale, CHU Nantes, Nantes, France.
Diane Doummar, Hôpital Trousseau, APHP.Sorbonne Université, Service de Neuropédiatrie, Paris, France.
Stéphanie Valence, Hôpital Trousseau, APHP.Sorbonne Université, Service de Neuropédiatrie, Paris, France.
Delphine Héron, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière-Hôpital Trousseau Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France.
Boris Keren, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière-Hôpital Trousseau Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France.
Cyril Mignot, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière-Hôpital Trousseau Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France.
Charles Coutton, Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, UMR 5309, CNRS, Université Grenoble Alpes, Inserm U1209, Grenoble, France.
Françoise Devillard, Service de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Anne-Sophie Alaix, Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, Paris, France.
Jeanne Amiel, Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, Paris, France.
Laurence Colleaux, Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, Paris, France.

Abstract

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.