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Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69-24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months-24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.

The X-linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a nonsyndromic monogenic form of autism spectrum disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD: c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an unfolded protein response, probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD.Copyright © 2019 Wiley Periodicals, Inc.

Primary Microcephalies (PMs) are characterized by a small head since birth, resulting from an insufficient production of mature neurons during neurogenesis. PMs carry a heavy burden of intellectual deficiency, and serve as model diseases for brain volumic development. Known PM genes are ascribed to several cellular pathways such as the centriole duplication pathway, the control of cellcycle checkpoints and the general control of DNA replication licensing, although the exact mechanisms remain unclear. Genes causing monogenic forms of PM can be identified in fewer than 50% of patients. Digenic inheritance has recently been described in the mouse for PM caused by Aspm and Wdr62, but it is not known whether this applies to humans. The genetic dissection of PM will provide interesting clues about the cellular mechanisms involved.In this study, we used two different holistic, in vivo approaches: high throughput DNA sequencing of multiple PM genes in human PM patients, and genome-edited zebrafish modeling of selected PM genes.Analysis of a large mostly outbred PM cohort revealed 15 novel mutations in known PM genes, ASPM and WDR62 being the most frequently mutated. Mutations in AP4M1 and TRAPPC9 were for the first time associated with PM in two families. A mutation in MCPH1 truncating the last BRCT domain was surprisingly not associated with PM. The analysis of the exome cohort also revealed variants in four candidate genes that are not yet associated with human pathologies. Furthermore, exomes of PM patients showed a significant excess of variants in 75 PM genes, that persisted after removing monogenic causes of PM. A PM gene panel showed that the burden was carried by six centrosomal genes. In zebrafish, non-centrosomal gene casc5 biallelic invalidation produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Digenic analysis of the PM cohort revealed candi, Les Microcéphalies Primaires (MPs) sont caractérisées par une tête trop petite dès la naissance, résultant d’une production insuffisante de neurones durant le développement embryonnaire. Les MPs sont responsables d’une lourde charge de déficits intellectuels, et servent de maladies modèles pour le développement volumique cérébral. Les gènes connus de MP appartiennent à des voies cellulaires distinctes, comme la duplication centriolaire, le contrôle du cycle cellulaire et le contrôle général de la réplication de l’ADN, bien que le mécanisme exact responsable des MP ne soit pas clair. Des gènes causant des formes monogéniques de MP sont identifiés dans moins de 50% des patients. Une hérédité digénique a récemment été décrite chez la souris pour la MP causée par Aspm et Wdr62, mais il n’est pas clair que ceci s’applique aussi à l’humain. La dissection génétique de la MP pourra fournir des informations intéressantes concernant les mécanismes cellulaires impliqués.Dans cette étude, nous avons utilisé deux approches holistiques, in vivo :séquençage à haut débit de multiples gènes de MP chez des patients MP humains, et invalidation de gènes sélectionnés de MP chez le poisson-zèbre.L’analyse d’une large cohorte de patients MP a révélé 15 nouvelles mutations dans des gènes MP connus, ASPM et WDR62 étant les gènes les plus fréquemment mutés. Des mutations dans les gènes AP4M1 et TRAPPC9 ont été associées à la MP dans deux familles. Une mutation dans le gène MCPH1 tronquant le dernier domaine BRCT n’a étonnamment pas été associée à la MP. L’analyse de la cohorte a aussi révélé des variants dans quatre gènes candidats n’ayant pas encore été associés à des pathologies humaines. De plus, l’analyse d’exomes de patients MP a montré un excès significatif de variants dans 75 gènes MP, persistant après retrait des causes monogéniques de MP. Un panel de gènes MP a montré que l’excès de variants était porté par six gènes centrosomaux. Chez le poisson-zèbre, l’invalidation biallélique du, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs*8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.