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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Development and Arealization of the Cerebral Cortex

Neuron, Journal Year: 2019, Volume and Issue: 103(6), P. 980 - 1004

Published: Sept. 1, 2019

Language: Английский

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Synaptic Specificity, Recognition Molecules, and Assembly of Neural Circuits

Cell, Journal Year: 2020, Volume and Issue: 181(3), P. 536 - 556

Published: April 1, 2020

Language: Английский

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A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Neuron, Journal Year: 2019, Volume and Issue: 101(6), P. 1070 - 1088

Published: March 1, 2019

Language: Английский

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The cell biology of synapse formation

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(7)

Published: June 4, 2021

In a neural circuit, synapses transfer information rapidly between neurons and transform this during transfer. The diverse computational properties of are shaped by the interactions pre- postsynaptic neurons. How assembled to form how specificity synaptic connections is achieved, largely unknown. Here, I posit that adhesion molecules (SAMs) organize synapse formation. Diverse SAMs collaborate achieve astounding plasticity synapses, with each SAM contributing different facets. orchestrating assembly, likely act as signal transduction devices. Although many candidate known, only few appear have major impact on Thus, limited set collaborating suffices account for Strikingly, several genetically linked neuropsychiatric disorders, suggesting impairments in assembly instrumental pathogenesis disorders.

Language: Английский

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Transplanting neural progenitor cells to restore connectivity after spinal cord injury

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(7), P. 366 - 383

Published: June 9, 2020

Language: Английский

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Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins

Science, Journal Year: 2019, Volume and Issue: 363(6429)

Published: Feb. 22, 2019

Coincidence detection in synaptogenesis In the brain, synaptic connections are formed with exquisite specificity, but underlying molecular mechanisms remain largely unexplored. Synapse formation is thought to involve bidirectional signaling by proteins that bind each other across cleft. Sando et al. used conditional genetic tools and vitro assays investigate of synapse formation. They found mouse hippocampus requires latrophilins. Latrophilins G protein–coupled receptors cell-surface called teneurins fibronectin leucine-rich repeat transmembrane (FLRTs). Two different latrophilins mediated distinct synapses on same hippocampal neuron. This function required binding both FLRTs. Thus, may guide coincidence signaling, which could help explain specificity connections. Science , this issue p. eaav7969

Language: Английский

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Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 505 - 518

Published: Nov. 6, 2020

Language: Английский

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Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions

Neuron, Journal Year: 2020, Volume and Issue: 109(2), P. 222 - 240

Published: Dec. 2, 2020

Language: Английский

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Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds

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

Published: June 6, 2019

Significant progress has been made in the treatment of spinal cord injury (SCI). Advances post-trauma management and intensive rehabilitation have significantly improved prognosis SCI converted what was once an "ailment not to be treated" into a survivable injury, but cold hard fact is that we still do validated method improve paralysis SCI. The irreversible functional impairment injured caused by disruption neuronal transduction across lesion, which brought about demyelination, axonal degeneration, loss synapses. Furthermore, refractory substrates generated inhibit spontaneous recovery. discovery regenerative capability central nervous system neurons proper environment verification neural stem cells incited hope cure for on horizon. That gradually replaced with mounting frustration when neuroprotective drugs, cell transplantation, strategies enhance remyelination, regeneration, plasticity demonstrated significant improvement animal models did translate human patients. However, recent advances research greatly increased our understanding fundamental processes underlying fostered increasing optimism these multiple are finally coming together bring new era will able propose encouraging therapies lead appreciable improvements In this review, outline pathophysiology makes regeneration discuss done replacement biomaterial implantation strategies, both itself as combined treatment. We focus capacity facilitate connectivity necessary achieve meaningful recovery after

Language: Английский

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