Caractérisation clinico-biologique approfondie de l’haploinsuffisance du gène MYT1L. Revue de la littérature et description d’une nouvelle cohorte de 31 patients

L’haploinsuffisance du gène MYT1L, en lien avec des délétions 2p25.3 ou des variations ponctuelles du gène, se caractérise par un trouble du neurodéveloppement commun (retard mental n°39, OMIM #616521) associant un retard de développement global prédominant sur le langage, une déficience intellectuelle de sévérité variable, une surcharge pondérale, des troubles du comportement et parfois une épilepsie. Cette pathologie, de transmission autosomique dominante, a été décrite dans la littérature chez environ 55 individus (34 délétions du gène et 21 variations ponctuelles). Nous nous sommes intéressés spécifiquement au phénotype associé aux variations ponctuelles, assez mal décrit dans la littérature, avec seulement deux cohortes de petite taille à ce jour, de 7 et 9 patients respectivement. Objectifs Les objectifs de ce travail étaient de proposer une version actualisée et précise de cette maladie causée par l’haploinsuffisance de MYT1L, tant sur le plan clinique que moléculaire. Pour cela, nous avons cherché à confirmer les signes cliniques caractéristiques et leur fréquence, d’élargir le phénotype, et enfin de rechercher de potentielles relations génotype-phénotype. Méthodes Dans un premier temps, nous avons colligé les descriptions cliniques de la littérature de manière exhaustive, chez les patients avec délétions et variations de séquence du gène. À la suite de cette revue, nous avons établi une nouvelle cohorte collaborative internationale de 31 patients présentant une variation pathogène du gène MYT1L. Résultats L’étude des données de la littérature a permis de confirmer que les variations ponctuelles et les délétions 2p25.3 emportant une partie ou la totalité de MYT1L sont à l’origine du même phénotype clinique que nous présentons en détail. Notre nouvelle cohorte nous a permis à la fois de confirmer les signes majeurs connus dans ce syndrome comme le retard de développement, la présence d’une déficience intellectuelle de sévérité variable, d’un autisme, d’un surpoids ou d’une obésité, d’une hyperphagie et d’une épilepsie, et par la même occasion d’apporter de nouveaux éléments descriptifs. Nous élargissons ainsi le phénotype associé à ce syndrome en rapportant les premiers patients sans déficience intellectuelle et les premiers patients présentant des difficultés alimentaires pendant l’enfance. Nous précisons les caractéristiques d’une dysmorphie faciale non constante. Sur le plan moléculaire, nous présentons 18 variations tronquantes et 13 variations faux-sens, dont 23 non encore décrites. Nous rapportons les premiers variants faux-sens de MYT1L présents en dehors des 2ème et 3ème domaines doigt de zinc de la protéine MYT1L, qui restent néanmoins les domaines cibles de la plupart des variations faux-sens pathogènes identifiées. Aucune relation génotype-phénotype n’a été mise en évidence, en particulier nous observons un phénotype similaire entre les patients avec variations tronquantes, et ceux avec variation faux-sens dans les deux domaines doigt de zinc, indiquant que ces faux-sens entrainent probablement une perte de fonction de la protéine. Conclusion En conclusion, l’élaboration de cette cohorte internationale de 31 patients nous permet d’apporter de plus amples connaissances concernant l’haploinsuffisance du gène MYT1L, dans l’objectif d’une meilleure prise en charge de ces patients au quotidien, à la fois sur le plan alimentaire mais également sur le plan neuropsychologique, et de pouvoir s’adapter dans la mesure du possible à leurs difficultés

Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations

International audienceCHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies

2p25.3 microduplications involving MYT1L: further phenotypic characterization through an assessment of 16 new cases and a literature review

International audienceMicroduplications involving the MYT1L gene have mostly been described in series of patients with isolated schizophrenia. However, few reports have been published, and the phenotype has still not been well characterized. We sought to further characterize the phenotypic spectrum of this condition by describing the clinical features of patients with a pure 2p25.3 microduplication that includes all or part of MYT1L. We assessed 16 new patients with pure 2p25.3 microduplications recruited through a French national collaboration (n = 15) and the DECIPHER database (n = 1). We also reviewed 27 patients reported in the literature. For each case, we recorded clinical data, the microduplication size, and the inheritance pattern. The clinical features were variable and included developmental and speech delays (33%), autism spectrum disorder (ASD, 23%), mild-to-moderate intellectual disability (ID, 21%), schizophrenia (23%), or behavioral disorders (16%). Eleven patients did not have an obvious neuropsychiatric disorder. The microduplications ranged from 62.4 kb to 3.8 Mb in size and led to duplication of all or part of MYT1L; seven of these duplications were intragenic. The inheritance pattern was available for 18 patients: the microduplication was inherited in 13 cases, and all parents but one had normal phenotype. Our comprehensive review and expansion of the phenotypic spectrum associated with 2p25.3 microduplications involving MYT1L should help clinicians to better assess, counsel and manage affected individuals. MYT1L microduplications are characterized by a spectrum of neuropsychiatric phenotypes with incomplete penetrance and variable expressivity, which are probably due to as-yet unknown genetic and nongenetic modifiers

uORF‐introducing variants in the 5′UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome

International audienceCornelia de Lange syndrome (CdLS) is a clinically-recognizable rare developmental disorder. About 70% of patients carry a missense or loss-of-function pathogenic variant in the NIPBL gene. We hypothesized that some variants in the 5'-untranslated region (UTR) of NIPBL may create an upstream open reading frame (uORF), putatively leading to a loss of function. We searched for NIPBL 5'-UTR variants potentially introducing uORF by (i) reannotating NGS data of 102 unsolved CdLS patients and (ii) literature and variant databases search. We set up a green fluorescent protein (GFP) reporter assay and studied NIPBL expression in a lymphoblastoid cell line (LCL). We identified two variants introducing a novel ATG codon sequence in the 5'-UTR of NIPBL, both predicted to introduce uORF: a novel c.-457_-456delinsAT de novo mutation in a 15-year-old male with classic CdLS, and a c.-94C>T variant in a published family. Our reporter assay showed a significant decrease of GFP levels in both mutant contexts, with similar levels of messenger RNA (mRNA) as compared to wt constructs. Assessment of LCL of one patient showed consistent results with decreased NIPBL protein and unchanged mRNA levels. 5'-UTR uORF-introducing NIPBL variants may represent a rare source of pathogenic variants in unsolved CdLS patients

Hum Mutat

Cornelia de Lange syndrome (CdLS; MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole genome sequencing (WGS) ± RNA sequencing (RNA-seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva-isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood-isolated RNA available. A pathogenic de novo mutation (DNM) was observed in a CdLS differential diagnosis gene in 3/5 patients, namely POU3F3, SPEN, and TAF1. In the other two, we identified two distinct deep intronic DNM in NIPBL predicted to create a novel splice site. RT-PCRs and RNA-Seq showed aberrant transcripts leading to the creation of a novel frameshift exon. Our findings suggest the relevance of WGS in unsolved suspected CdLS cases and that deep intronic variants may account for a proportion of them

Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Full accessInternational audienceSirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder

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

International audiencePathogenic 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

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

International audiencePathogenic 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

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

International audiencePathogenic 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

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

International audiencePathogenic 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