scholarly journals Three case reports of patients indicating the diversity of molecular and clinical features of 16p11.2 microdeletion anomaly

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Monika Szelest ◽  
Martyna Stefaniak ◽  
Gabriela Ręka ◽  
Ilona Jaszczuk ◽  
Monika Lejman
Keyword(s):  
System Development ◽  
Case Reports ◽  
Genetic Diagnosis ◽  
Health Assessment ◽  
Interdisciplinary Approach ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Language Delays ◽  
Motor Delay ◽  
Deletion Diagnostics

Abstract Background 16p11.2 microdeletion is a known chromosomal anomaly associated mainly with neurocognitive developmental delay, predisposition to obesity, and variable dysmorphism. Although this deletion is relatively rare among the general population, it is one of the serious known genetic aetiologies of obesity and autism spectrum disorder. Case presentation This study presents three cases of deletions within the 16p11.2 region. Every child had mild variable craniofacial abnormalities, hand or foot anomalies and developmental and language delays. The first proband had obesity, epilepsy, moderate intellectual disability, aphasia, motor delay, hyperinsulinism, and café au lait spots. The second proband suffered from cardiac, pulmonary, and haematological problems. The third proband had motor and language delays, bronchial asthma, and umbilical hernia. Although each patient presented some features of the syndrome, the children differed in terms of their clinical pictures. Genetic diagnosis of 16p11.2 microdeletion syndrome was made in children at different ages based on multiplex ligation probe-dependent amplification analysis and/or microarray methods. Conclusions Our reports allow us to analyse and better understand the biology of 16p11.2 microdeletion throughout development. However, the variability of presented cases supports the alternate conclusion to this presented in available literature regarding 16p11.2 deletion, as we observed no direct cause-and-effect genotype/phenotype relationships. The reported cases indicate the key role of the interdisciplinary approach in 16p11.2 deletion diagnostics. The care of patients with this anomaly is based on regular health assessment and adjustment of nervous system development therapy.

scholarly journals Epigenomic Convergence of Neural-Immune Risk Factors in Neurodevelopmental Disorder Cortex

2019 ◽  
Vol 30 (2) ◽  
pp. 640-655 ◽  
Author(s):  
A Vogel Ciernia ◽  
B I Laufer ◽  
H Hwang ◽  
K W Dunaway ◽  
C E Mordaunt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cytosine Methylation ◽  
System Development ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Developed Countries ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Human Cortex ◽  
Genes And Environment

Abstract Neurodevelopmental disorders (NDDs) affect 7–14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into NDD etiology. Whole-genome bisulfite sequencing was used to examine DNA cytosine methylation in 49 human cortex samples from 3 different NDDs (autism spectrum disorder, Rett syndrome, and Dup15q syndrome) and matched controls. Integration of methylation changes across NDDs with relevant genomic and genetic datasets revealed differentially methylated regions (DMRs) unique to each type of NDD but with shared regulatory functions in neurons and microglia. NDD DMRs were enriched within promoter regions and for transcription factor binding sites with identified methylation sensitivity. DMRs from all 3 disorders were enriched for ontologies related to nervous system development and genes with disrupted expression in brain from neurodevelopmental or neuropsychiatric disorders. Genes associated with NDD DMRs showed expression patterns indicating an important role for altered microglial function during brain development. These findings demonstrate an NDD epigenomic signature in human cortex that will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental NDD risk factors.

Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

2017 ◽  
Vol 29 (2) ◽  
Author(s):  
Timothy R. Rice
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodevelopmental Disorders ◽  
System Development ◽  
Explanatory Power ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Special Focus ◽  
Important Mediator ◽  
Androgen Exposure

Abstract Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

scholarly journals Spatiotemporal expression of IgLON family members in the developing mouse nervous system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sydney Fearnley ◽  
Reesha Raja ◽  
Jean-François Cloutier
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Developmental Disorders ◽  
System Development ◽  
Expression Patterns ◽  
Family Members ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Spatiotemporal Expression ◽  
Developing Nervous System

AbstractDifferential expression of cell adhesion molecules in neuronal populations is one of the many mechanisms promoting the formation of functional neural circuits in the developing nervous system. The IgLON family consists of five cell surface immunoglobulin proteins that have been associated with various developmental disorders, such as autism spectrum disorder, schizophrenia, and major depressive disorder. However, there is still limited and fragmented information about their patterns of expression in certain regions of the developing nervous system and how their expression contributes to their function. Utilizing an in situ hybridization approach, we have analyzed the spatiotemporal expression of all IgLON family members in the developing mouse brain, spinal cord, eye, olfactory epithelium, and vomeronasal organ. At one prenatal (E16) and two postnatal (P0 and P15) ages, we show that each IgLON displays distinct expression patterns in the olfactory system, cerebral cortex, midbrain, cerebellum, spinal cord, and eye, indicating that they likely contribute to the wiring of specific neuronal circuitry. These analyses will inform future functional studies aimed at identifying additional roles for these proteins in nervous system development.

scholarly journals Spatiotemporal transcriptomic divergence across human and macaque brain development

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat8077 ◽  
Author(s):  
Ying Zhu ◽  
André M. M. Sousa ◽  
Tianliuyun Gao ◽  
Mario Skarica ◽  
Mingfeng Li ◽  
...  
Keyword(s):  
Brain Development ◽  
System Development ◽  
Brain Regions ◽  
Tissue Level ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Functional Hierarchy ◽  
Topographic Gradients ◽  
Shed Light ◽  
Human Nervous System

Human nervous system development is an intricate and protracted process that requires precise spatiotemporal transcriptional regulation. We generated tissue-level and single-cell transcriptomic data from up to 16 brain regions covering prenatal and postnatal rhesus macaque development. Integrative analysis with complementary human data revealed that global intraspecies (ontogenetic) and interspecies (phylogenetic) regional transcriptomic differences exhibit concerted cup-shaped patterns, with a late fetal-to-infancy (perinatal) convergence. Prenatal neocortical transcriptomic patterns revealed transient topographic gradients, whereas postnatal patterns largely reflected functional hierarchy. Genes exhibiting heterotopic and heterochronic divergence included those transiently enriched in the prenatal prefrontal cortex or linked to autism spectrum disorder and schizophrenia. Our findings shed light on transcriptomic programs underlying the evolution of human brain development and the pathogenesis of neuropsychiatric disorders.

scholarly journals Ocular Phenotype Associated with DYRK1A Variants

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 234
Author(s):  
Cécile Méjécase ◽  
Christopher M. Way ◽  
Nicholas Owen ◽  
Mariya Moosajee
Keyword(s):  
Intellectual Disability ◽  
System Development ◽  
International Association ◽  
Care Pathway ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Self Report ◽  
Dual Specificity ◽  
The Uk

Dual-specificity tyrosine phosphorylation-regulated kinase 1A or DYRK1A, contributes to central nervous system development in a dose-sensitive manner. Triallelic DYRK1A is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare DYRK1A-related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for DYRK1A in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a DYRK1A pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous DYRK1A variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with DYRK1A variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life.

A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia

2021 ◽  
Author(s):  
Claudia Ciaccio ◽  
Emanuela Leonardi ◽  
Roberta Polli ◽  
Alessandra Murgia ◽  
Stefano D'Arrigo ◽  
...  
Keyword(s):  
De Novo ◽  
System Development ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Underlying Mechanism ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Cerebellar Hypoplasia ◽  
Hyperactivity Disorder ◽  
The Central Nervous System

Abstract KIRREL3 is a gene important for the central nervous system development—in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis—and colocalizes and cooperates in neurons with CASK gene. Alterations of KIRREL3 have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of KIRREL3 partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo KIRREL3 mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant KIRREL3 variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between KIRREL3 and CASK, we discuss as posterior fossa anomalies may also be part of the phenotype of KIRREL3-related syndrome.

scholarly journals The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines

2014 ◽  
Vol 4 (3) ◽  
pp. e374-e374 ◽  
Author(s):  
M Pathania ◽  
E C Davenport ◽  
J Muir ◽  
D F Sheehan ◽  
G López-Doménech ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
System Development ◽  
Significant Risk ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Actin Dynamics ◽  
Expression Levels ◽  
Dendritic Complexity

Abstract Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.

Effect of afobazole on early postnatal changes in BALB/c mice with fetal valproate syndrome

2021 ◽  
pp. 12-21
Author(s):  
И.Г. Капица ◽  
А.А. Алымов ◽  
Т.А. Воронина ◽  
С.Б. Середенин
Keyword(s):  
Valproic Acid ◽  
Sodium Chloride ◽  
Postnatal Development ◽  
Motor Behavior ◽  
System Development ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Control Group ◽  
Fetal Valproate Syndrome ◽  
Sensory Motor

Введение. Воздействие вальпроевой кислотой во время беременности у грызунов широко используется для моделирования расстройств аутистического спектра (РАС). Цель исследования - изучение ранних поведенческих изменений у мышей BALB/c, пренатально подвергшихся однократному воздействию натриевой соли вальпроевой кислоты (400 мг/кг), и возможности их коррекции афобазолом. Методика. Объект исследования - мыши линии BALB/c с фетальным вальпроат-синдромом (ФВС), которым с 7-х по 14-е сут постнатального развития перорально ежедневно вводили афобазол (10 мг/кг) или 0,9% раствор хлорида натрия. Контрольная группа получала 0,9% раствор хлорида натрия в эквивалентном объеме (0,1 мл на 10 г массы). Состояние мышат изучали с 6-х по 14-е сут постнатального развития, оценивали их физическое развитие, скорость созревания сенсорно-двигательных рефлексов, эмоционально-двигательное поведение и точную координацию движений при помощи батареи «развитийных» тестов. Результаты. Введение самкам мышей на 13-й день беременности вальпроевой кислоты приводило к отставанию созревания у потомства сенсорно-двигательных рефлексов, нарушению эмоционально-двигательного поведения и координации движений в гнездовом периоде. Афобазол, при введении 10 мг/кг перорально ежедневно, начиная с 7-х сут постнатального развития мышам с ФВС, корригировал отмеченные нарушения в тестах, отражающих нарушения развития нервной системы. Заключение. Установлены корригирующие свойства афобазола в отношении нарушений, вызванных пренатальным введением ВПК, что определяет целесообразность дальнейшего изучения афобазола на моделях РАС. Introduction. Exposure of rodents to valproic acid during pregnancy is associated with increased incidence of autism spectrum disorders, and has been extensively used as an appropriate model of autism. Aim. To study early behavioral changes in BALB/c mice prenatally exposed to a single dose of valproic acid sodium salt (400 mg/kg) and a possibility of correcting these changes with afobazole. Methods. The study was performed on BALB/c mice with fetal valproate syndrome (FVS). The mice were daily injected orally afobazole 10 mg/kg or 0.9% sodium chloride from day 7 to day 14 of the postnatal development. The control group was injected with an equivalent volume (0.1 ml per 10 g body weight) of 0.9% sodium chloride. The condition of mice was studied from day 6 to day 14 of the postnatal development with evaluation of their physical development, maturation rate of sensory-motor reflexes, emotional-motor behavior, and precise coordination using a battery of «developmental» tests. Results. Administration of valproic acid to female mice on the 13th day of pregnancy led to delayed maturation of the offspring’s sensory-motor reflexes, impaired emotional-motor behavior and coordination of movements during the nesting period. Afobazole administered to mice with fetal valproate syndrome from day 7 to day 14 of the postnatal development at a dose of 10 mg/kg (daily, orally), corrected the disorders in the tests used for assessing retardation or disruption of nervous system development.

scholarly journals Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

2016 ◽  
Vol 4 (1) ◽  
pp. 1-19 ◽  
Author(s):  
Shikshya Shrestha ◽  
Steven M. Offer
Keyword(s):  
Brain Development ◽  
Neurological Disorders ◽  
System Development ◽  
Neuronal Cell ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Adult Brain ◽  
Epigenetic Therapy ◽  
Gabaergic Neurotransmission ◽  
Epigenetic Regulations

The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotransmission, both excitatory and inhibitory, in neurogenesis and central nervous system development including its control of neuronal cell proliferation and migration, synaptogenesis, dendrite formation and branching, and new neuronal cell integration in the adult brain. There has been remarkable progress in understanding the epigenetic regulations of GABAergic genes and their aberrant expressions in various neurological disorders such as autism spectrum disorder, Rett's syndrome, schizophrenia and PWS. The roles of histone modifications, chromatin looping and gene methylation have been implicated in altered regulations of key genes in the GABAergic pathway. Taken together, they affect the functioning of GABAergic neurotransmission and disrupt various events in brain development. Here, we focus on the role of GABAergic neurotransmission in brain development and on how various genetic and epigenetic events regulate the GABAergic genes in pre- and postnatal brain. We also discuss how these regulatory mechanisms contribute to the pathogenesis of neurological disorders and, therefore, can be used in the development of potential epigenetic therapy for these diseases.

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