Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

Cell, Journal Year: 2019, Volume and Issue: 176(4), P. 743 - 756.e17

Published: Feb. 1, 2019

Language: Английский

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Genetic Causes and Modifiers of Autism Spectrum Disorder

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Aug. 20, 2019

Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD highly genetically heterogeneous and may be caused by both inheritable de novo gene variations. In past decade, hundreds genes have been identified that contribute to serious deficits communication, social cognition, behavior patients often experience. However, these only account for 10-20% cases, with similar pathogenic variants diagnosed on very different levels spectrum. this review, we will describe genetic landscape discuss how modifiers such as copy number variation, single nucleotide polymorphisms, epigenetic alterations likely play a key role modulating phenotypic spectrum patients. We also consider can alter convergent signaling pathways lead impaired neural circuitry formation. Lastly, review sex-linked clinical implications. Further understanding mechanisms crucial comprehending developing novel therapies.

Language: Английский

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Neurodevelopmental Disorders: From Genetics to Functional Pathways

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(8), P. 608 - 621

Published: June 5, 2020

NDDs are caused by the disruption of essential neurodevelopmental processes. Many genes and mutations associated with NDDs, pointing to a heterogeneous origin these disorders.Genotype–phenotype correlations difficult establish due existence multiple genetic as well environmental factors that influence phenotypical outcome. The two-hit model molecular diagnoses important should be taken into account when addressing NDDs.Most known belong few common frequently affected pathways. Functional studies elucidating how different can disturb converging pathways lead identification potential targets, thereby opening perspectives for future treatment. Neurodevelopmental disorders (NDDs) class affecting brain development function characterized wide clinical variability. In this review, we discuss presentation particular attention gene vulnerability, mutational load, model. Despite complex architecture events various proteins involved appear converge on pathways, such synaptic plasticity/function, chromatin remodelers mammalian target rapamycin (mTOR) pathway. A thorough understanding mechanisms behind will hopefully candidates could targeted treatment approaches. an inability reach cognitive, emotional, motor developmental milestones. Typically, tightly coordinated development. constitute serious health problem in our society, >3% children worldwide [1.Gilissen C. et al.Genome sequencing identifies major causes severe intellectual disability.Nature. 2014; 511: 344-347Crossref PubMed Scopus (573) Google Scholar]. They have etiology impaired cognition, communication, adaptive behavior, psychomotor skills. include autism spectrum disorder (ASD), disability (ID), deficit hyperactivity disorder, epilepsy [2.Niemi M.E.K. al.Common variants contribute risk rare disorders.Nature. 2018; 562: 268-271Crossref (63) Scholar,3.Tărlungeanu D.C. Novarino G. Genomics disorders: avenue personalized medicine.Exp. Mol. Med. 50: 1-7Crossref (5) suggested shared signs characterize [4.Cristino A.S. al.Neurodevelopmental neuropsychiatric represent interconnected system.Mol. Psychiatry. 19: 294-301Crossref (103) Scholar,5.Hormozdiari F. al.The discovery integrated networks related disorders.Genome Res. 2015; 25: 142-154Crossref (123) Accordingly, comorbidity (see Glossary) two or more is observed. For instance, combination ID, ASD, commonly reported individual patients [6.van Bokhoven H. Genetic epigenetic disabilities.Annu. Rev. Genet. 2011; 45: 81-104Crossref (203) Scholar,7.Du X. al.Genetic diagnostic evaluation trio-based whole exome among diagnosed suspected disorder.Front. 9: 594Crossref Identification pathogenic help explain aforementioned eventually effective terms genetics, types mutation been including chromosomal rearrangements, copy number variations, small indels, point mutations. Thus, underlying event, diagnosis, challenging task needs overcome heterogeneity array variations. Some technologies currently used diagnosis summarized Box 1.Box 1Evolution Diagnostic Flowchart NDDsEarly NDD counseling, patient management, medical intervention.Previously, G banded karyotype FMR1 trinucleotide repeat analysis were recommended first-tier test unexplained NDDs. However, yield was low [111.Blesson A. Cohen J.S. counseling disorders.Cold Spring Harb. Perspect. 2019; 10: a036533Google breakthrough next-generation has led significant advancements Scholar,112.Carneiro T.N. al.Utility elucidation basis isolated syndromic disability: illustrative cases.Appl. Clin. 11: 93-98Crossref (7) To date, >900 responsible X-linked, autosomal dominant, recessive [113.Chiurazzi P. Pirozzi Advances - disability.F1000Res. 2016; 5 (Faculty Rev-599): F1000Crossref (37) Scholar,114.Wright C.F. DDD study: scalable genome-wide research data.Lancet. 385: 1305-1314Abstract Full Text PDF (315) Due correlation protein-coding genes, cheaper quicker whole-exome (WES) preferred tool informative whole-genome [115.Clark M.M. al.Meta-analysis utility genome microarray diseases.NPJ Genom. 3: 16Crossref (71) Scholar,116.Srivastava S. multidisciplinary consensus statement: individuals disorders.Genet. 21: 2413-2421Abstract (32) Different highlighted efficiency tool, having up >40% especially both biological parents considered Scholar] Still, also occur noncoding regions, regulatory elements, alter expression levels DNA microarrays detect gross aberrations otherwise not detectable conventional WES [117.Martin C.L. Ledbetter D.H. Chromosomal testing disorders.JAMA. 2017; 317: 2545-2546Crossref Scholar,118.Bhattacharya S.K. al.Chromosomal uncovers variations congenital anomalies.J. Biomed. Sci. 8: 3Google expected estimated ~10–20% distinct Epigenetic alterations, escaping detection, observed presence Therefore, additional methods changes, PCR, tandem mass spectrometry, southern blot. Early intervention. Previously, These challenges notwithstanding, recognition NDD-causing crucial accurate represents first step toward better disorders. This review focuses starting from genetics moving functional level. First, study familial cases improved Second, consider determine phenotype, diagnoses. We highlight relevance context Finally, debate whether cellular allows circumventing issue variability open treatments. vital onset delineation genotype–phenotype monitor progress foresee complications. numerous NDD-causative identified, many still do receive diagnosis. Additionally, phenotype–genotype brought light severity vary substantially overlapping [8.Li Y. al.Genotype phenotype SHANK3 de novo disorders.Am. J. 176: 2668-2676PubMed Scholar,9.Casanova E.L. al.Widespread genotype-phenotype disability.Front. 9535–535Crossref missing heritability multifactorial and/or polygenic nature Familial useful paradigm dissecting contribution nongenetic pathogenesis background. reason, conducted monozygotic twins discordant phenotypes [10.Huang al.Identifying genomic using sequencing.Mol. Ther. Nucleic Acids. 14: 204-211Abstract (4) Scholar, 11.Willfors al.Medical history etiologies autism.Transl. 7e1014Crossref (10) 12.Radley J.A. al.Deep phenotyping 14 new IQSEC2 variants, phenotype.Clin. 95: 496-506Crossref pedigrees where incomplete penetrance offspring [13.Karaca E. al.Phenotypic expansion illuminates multilocus variation.Genet. 20: 1528-1537Abstract (33) line tremendous only mere disease, but protective factors. Furthermore, it establishing correlations. Thanks inherited emerged outcome essentially revolves around main principles: vulnerability load (Figure 1A ). Gene defined capability given tolerate disruptive variants: lower tolerance towards mutations, higher level vulnerability. haploinsufficient striking dosage sensitivity. fall within category highly vulnerable disease risk. Examples DEPDC5, CACNA1A, SCN8A, which discussed later section. Disruption one high probability inducing absence other causative events, thus resulting monogenic forms [14.Iossifov I. al.Low their biased transmission.Proc. Natl. Acad. U. 112: E5600-E5607Crossref (58) normally subject strong negative selective pressure. Hence, population recognized reduced compared loci words, categorized penetrance. end comprises those less sensitive Variants under pressure transmitted families generations Scholar,14.Iossifov Since single nonvulnerable causing per se, they Nonetheless, recent demonstrated portion attributed Scholar,15.Kurki M.I. al.Contribution sub-isolate Northern Finland.Nat. Commun. 410Crossref (6) fact, additive effects result Scholar,16.Pizzo L. al.Rare background modulate cognitive carrying disease-associated variants.Genet. 816-825Abstract (26) cases, however, depends sum physical interactions between (i.e., epistasis) [17.Mitra al.Reverse pathway approach epistasis disorders.PLoS 13e1006516Crossref (19) Scholar,18.Iyer al.Pervasive defects autism-associated 16p11.2 deletion Drosophila melanogaster.Nat. 2548Crossref (13) Epistatic sensitivity strongly correlate concept argues complexity influenced events. example, loss-of-function monoallelic sodium channels CACNA1A SCN8A variety features movement benign infantile seizures 1B) [19.Reinson K. al.Biallelic cause early epileptic encephalopathy progressive cerebral, cerebellar, optic nerve atrophy.Am. 170: 2173-2176Crossref Scholar,20.Wengert E.R. SCN8A-related encephalopathy.Epilepsia. 60: 2277-2285Crossref (2) accordance criteria germline biallelic changes 1C) recently compound heterozygous probands encephalopathy, while siblings exhibit mild impairment without seizure might determined somatic mechanism classic hypothesis, constitutive generates subsequent hit occurring during then already present 1E). One example comes DEPDC5. Germline DEPDC5 refractory focal epilepsies [21.Ribierre T. al.Second-hit mosaic mTORC1 repressor cortical dysplasia-associated epilepsy.J. Investig. 128: 2452-2458Crossref (0) second variant inactivation found dysplasia Scholar,22.Lee W.S. limited dysmorphic neurons type IIA.Ann. Transl. Neurol. 6: 1338-1344Crossref (1) Primary secondary at each other, expanding hypothesis 1D). Several unveiled Scholar,23.Guo al.Inherited autism/developmental delay suggest model.Mol. Autism. 64Crossref (16) 24.Posey J.E. al.Resolution variation.N. Engl. 376: 21-31Crossref (246) 25.Liu al.Reanalysis data.N. 380: 2478-2480Crossref notion analyses established likely [23.Guo disrupting positively correlates Scholar,24.Posey dissected intrafamilial families, explained severely cumulative makes pathological 1F). burden correlated predisposition educational attainment ID data available literature purely exception rather than rule. Most most nature, hence confirming broad Importantly, factors, although discussion beyond scope current review. implementation (NGS) flowchart dramatically increased percentage who ramifications since assessment recurrence gives possibility advances field served roadmap aimed As next, elucidated some offers opportunity complexities variability, develop therapeutic performed past decade shown affect role conserved [26.Sahin M. Sur Genes, circuits, precision therapies disorders.Science. 350aab3897Crossref (108) 27.Parikshak N.N. al.Integrative

Language: Английский

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Dendritic structural plasticity and neuropsychiatric disease

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(4), P. 215 - 234

Published: March 16, 2018

Language: Английский

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Autism genes converge on asynchronous development of shared neuron classes

Nature, Journal Year: 2022, Volume and Issue: 602(7896), P. 268 - 273

Published: Feb. 2, 2022

Language: Английский

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Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

Nature Genetics, Journal Year: 2018, Volume and Issue: 51(1), P. 106 - 116

Published: Dec. 7, 2018

Language: Английский

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The ASD Living Biology: from cell proliferation to clinical phenotype

Molecular Psychiatry, Journal Year: 2018, Volume and Issue: 24(1), P. 88 - 107

Published: June 19, 2018

Abstract Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and lay public because its uncertain origins striking unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, cell model evidence that shows ASD begins in womb. This leads to a new theory is multistage, progressive brain development, spanning nearly all prenatal life. can begin as early 1st 2nd trimester with disruption proliferation differentiation. It continues neural migration, laminar disorganization, altered neuron maturation neurite outgrowth, synaptogenesis reduced network functioning. Among most commonly reported high-confidence ( hcASD ) genes, 94% express during life affect these fetal processes neocortex, amygdala, hippocampus, striatum cerebellum. A majority genes are pleiotropic, proliferation/differentiation and/or synapse development. Proliferation subsequent stages also be disrupted by maternal immune activation trimester. Commonly implicated pathways, PI3K/AKT RAS/ERK, pleiotropic multiple from through functional In different individuals, variation how when pathways dysregulated, will lead different, even opposing effects, producing well later Thus, pathogenesis not set at one point time does reside process, but rather cascade pathogenic vast toddlers. Despite this knowledge biology womb, current research methods have provided individualized information: What early-age molecular cellular differences underlie each individual child? Without such knowledge, rapid advances biological-based diagnostic, prognostic, precision medicine treatments cannot occur. Missing, therefore, what call Living Biology. conceptual paradigm shift towards focus on abnormal underlying within living individual. The concept emphasizes specific need for foundational child’s development beginnings stages. Biology seeks linking genetic vitro molecular, measurements vivo post-natal presentation progression child. We first study, which confirms multistage nature provides fetal-stage explanation overgrowth. Within-child novel coin here advocates integration information generate group-level explanations, clinically useful prognoses, approaches truly beneficial infant toddler ASD.

Language: Английский

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PSD95: A synaptic protein implicated in schizophrenia or autism?

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2017, Volume and Issue: 82, P. 187 - 194

Published: Nov. 22, 2017

Language: Английский

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Synaptopathology Involved in Autism Spectrum Disorder

Frontiers in Cellular Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Dec. 21, 2018

Autism spectrum disorder (ASD) is a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, interaction and repetitive behaviors. ASD affected 1 in 59 children, about 4 times more common among boys than girls. There strong genetic component to susceptibility, conjunction with developmental early environmental factors, together contribute the pathogenesis ASD. Multiple studies have unveiled that mutations genes like NRXN, NLGN, SHANK, TSC1/2, FMR1 MECP2 converge on cellular pathways intersect at synapses. These gene products encompass cell adhesion molecules, scaffolding proteins, regulators transcription protein levels, affecting synapses various aspects including synapse formation elimination, synaptic transmission plasticity, which suggests ASD, least part, be attributed dysfunction. In this review article, we focus major signaling implicated abnormalities underlying discuss molecular, functional animal models.

Language: Английский

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Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

The American Journal of Human Genetics, Journal Year: 2017, Volume and Issue: 102(1), P. 175 - 187

Published: Dec. 21, 2017

Language: Английский

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