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Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global psychomotor delay and intellectual disability. Low birth weight, growth restriction with feeding difficulties, stature insufficiency, and microcephaly are frequently reported. This study aims to create specific growth charts for individuals with DYRK1A Syndrome and identify parameters for size prognosis. Growth parameters were obtained for 92 individuals with DYRK1A Syndrome (49 males vs. 43 females). The data were obtained from pediatric records, parent reporting, and scientific literature. Growth charts for height, weight, body mass index (BMI), and occipitofrontal circumference (OFC) were generated using generalized additive models through R package gamlss. The growth curves include height, weight, and OFC measurements for patients aged 0-5 years. In accordance with the literature, the charts show that individuals are more likely to present intrauterine growth restriction with low birth weight and microcephaly. The growth is then characterized by severe microcephaly, low weight, and short stature. This study proposes growth charts for widespread use in the management of patients with DYRK1A syndrome., (© 2023 Wiley Periodicals LLC.)

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene., (© 2022 Wiley Periodicals LLC.)

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability., (© 2022. The Author(s).)

Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics., Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature., Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice., Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autosomal recessive primary microcephaly results from abnormal brain development linked to proliferation defects in neural progenitors. The most frequent form, caused by ASPM mutations, is usually defined by a reduced brain volume and is associated with intellectual disability. Although many ASPM cases have now been reported, structural brain abnormalities and their link with cognitive disabilities have rarely been investigated. In this study, we used high resolution T1-weighted magnetic resonance imaging in seven patients with ASPM mutations and 39 healthy age-matched controls to quantify regional volumes, thickness, surface area, gyrification index and white matter volumes of 30 cortical regions. We observed a consistent reduction of 50% or more in the volume and surface area of all cortical regions except for the hippocampus and surrounding medial temporal structures, which were significantly less reduced. Neuropsychologic assessment indicated significant impairments of cognitive abilities. However, these impairments were associated with normal mnesic abilities, in keeping with the relative preservation of the hippocampus and medial temporal structures. These results show that, contrary to current opinion, the cortical volume and surface area of patients with ASPM mutations is reduced depending on a regionally specific fashion and their cognitive profile reflects this heterogeneity. The precise characterization of the cortical map and cognitive abilities of patients with ASPM mutations should allow developing more focused reeducative interventions well-suited to their real abilities., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome., (Copyright © 2013 Wiley Periodicals, Inc.)

Microcephaly-capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.

Background: Heterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia., Methods: The study characterised the CASK alteration in 20 new female patients by molecular karyotyping, fluorescence in situ hybridisation, sequencing, reverse transcriptase (RT) and/or quantitative real-time PCR. Clinical and brain imaging data of a total of 25 patients were reviewed., Results: 11 submicroscopic copy number alterations, including nine deletions of ~11 kb to 4.5 Mb and two duplications, all covering (part of) CASK, four splice, four nonsense, and one 1 bp deletion are reported. These heterozygous CASK mutations most likely lead to a null allele. Brain imaging consistently showed diffuse brainstem and cerebellar hypoplasia with a dilated fourth ventricle, but of remarkably varying degrees. Analysis of 20 patients in this study, and five previously reported patients, revealed a core clinical phenotype comprising severe developmental delay/intellectual disability, severe postnatal microcephaly, often associated with growth retardation, (axial) hypotonia with or without hypertonia of extremities, optic nerve hypoplasia, and/or other eye abnormalities. A recognisable facial phenotype emerged, including prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and/or large ears., Conclusions: These findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.

Background: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types., Methods and Results: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype., Conclusion: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Objective: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations., Methods: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family., Results: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1)., Conclusions: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

The article presents the case of a child patient with severe neonatal-onset pustular psoriasis that is recurrently exacerbated. He also experienced high fever related to complex developmental syndrome such as microcephaly, aortic stenosis and osteomyelitis. He was diagnosed with generalized pustular psoriasis (GPP), which is a severe inflammatory skin disease.