MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects
2 GeneDx [Gaithersburg, MD, USA]
3 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
4 UBFC - Université Bourgogne Franche-Comté [COMUE]
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 IGMA - Institut de génétique médicale d’Alsace
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
8 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
9 SU - Sorbonne Université
10 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
11 CHUGA - CHU de Grenoble-Alpes - Centre Hospitalier Universitaire CHU Grenoble
12 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
13 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
14 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
15 Ghent University Hospital
16 CUIMC - Columbia University Irving Medical Center
17 University of Colorado Anschutz Medical Campus [Aurora]
18 University of Tennessee System
19 NJMS - Rutgers New Jersey Medical School
20 Université de Lille
21 TIMONE - Hôpital de la Timone [CHU - APHM]
22 CHU Montpellier = Montpellier University Hospital
23 Maine Medical Center
24 Arnold Palmer Hospital
25 Boston Children's Hospital
26 National Center of Genetics
27 CNRGH - Centre National de Recherche en Génomique Humaine
28 CHU Pitié-Salpêtrière [AP-HP]
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Résumé
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.
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