Evidence for 28 genetic disorders discovered by combining healthcare and research data

Nature, Journal Year: 2020, Volume and Issue: 586(7831), P. 757 - 762

Published: Oct. 14, 2020

Language: Английский

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Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(9), P. 1320 - 1331

Published: Aug. 18, 2022

Language: Английский

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Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(1), P. 445 - 465

Published: April 19, 2021

Language: Английский

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Artificial intelligence for precision medicine in neurodevelopmental disorders

npj Digital Medicine, Journal Year: 2019, Volume and Issue: 2(1)

Published: Nov. 21, 2019

The ambition of precision medicine is to design and optimize the pathway for diagnosis, therapeutic intervention, prognosis by using large multidimensional biological datasets that capture individual variability in genes, function environment. This offers clinicians opportunity more carefully tailor early interventions- whether treatment or preventative nature-to each patient. Taking advantage high performance computer capabilities, artificial intelligence (AI) algorithms can now achieve reasonable success predicting risk certain cancers cardiovascular disease from available clinical data. In contrast, less progress has been made with neurodevelopmental disorders, which include intellectual disability (ID), autism spectrum disorder (ASD), epilepsy broader disorders. Much hope pinned on quantify patterns genomic variation, including functional characterization genes variants, but this confounded phenotypic etiologic heterogeneity, along rare variable penetrant nature underlying variants identified so far. Structural brain imaging neuropsychological neurophysiological markers may provide further dimensionality, often require development sensitivity diagnosis. Herein, therefore, lies a conundrum: offer breakthrough risks disorders? review we will examine these complexities, consider some strategies whereby overcome them.

Language: Английский

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Human brain organogenesis: Toward a cellular understanding of development and disease

Cell, Journal Year: 2021, Volume and Issue: 185(1), P. 42 - 61

Published: Nov. 11, 2021

Language: Английский

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 1, 2020

Most genes associated with neurodevelopmental disorders (NDDs) were identified an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 16,294 NDD cases and additional 62 6,211 cases. By combining these published data, assess a total 125 over 16,000 compare to nonpsychiatric controls from ExAC. We identify 48 (25 newly reported) showing significant ultra-rare (MAF < 0.01%) gene-disruptive (FDR 5%), six which reach family-wise error rate (FWER) (p 1.25E-06). Among targeted genes, also reevaluate DNM 17,426 trios 6,499 new autism trios. 90 enriched for DNMs 5%; e.g., GABRG2 UIMC1); which, 61 FWER 3.64E-07; CASZ1). In addition doubling number patients many risk present phenotype-genotype correlations seven (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, LEO1) based on this large-scale sequencing effort.

Language: Английский

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Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility

Science, Journal Year: 2020, Volume and Issue: 370(6523)

Published: Dec. 18, 2020

A high-quality rhesus macaque genome Genome technology has improved substantially since the first full organismal genomes were generated. Applying new technology, Warren et al. refined of macaque, a model nonhuman primate. Long-read and other recent advances in sequencing applied to generate with far fewer gaps helped refine locations numbers repetitive elements. Furthermore, authors performed resequencing among populations identify genetic variability macaque. Thus, previously incomplete inaccurate set sequence information is now fully resolved, improving gene mapping for biomedical comparative studies. Science , this issue p. eabc6617

Language: Английский

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Insufficient Evidence for “Autism-Specific” Genes

The American Journal of Human Genetics, Journal Year: 2020, Volume and Issue: 106(5), P. 587 - 595

Published: April 30, 2020

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest identifying that, when mutated, confer risk is largely specific for autism spectrum disorder (ASD). Here, we review findings limitations of recent efforts to identify relatively "autism-specific" genes, which focus on rare large effect size thought account observed phenotypes. We present a divergent interpretation published evidence; discuss practical theoretical issues related studying relationships between rare, large-effect phenotypes; describe potential future directions this research. argue currently insufficient establish meaningful ASD specificity any based rare-variant data. Autism (ASD) clinically etiologically heterogeneous, unifying pathophysiology not yet identified either as whole or its core behavioral components. Heritability estimates high (0.65–0.91) family twin studies,1Sandin S. Lichtenstein P. Kuja-Halkola R. Larsson H. Hultman C.M. Reichenberg A. The familial autism.JAMA. 2014; 311: 1770-1777Crossref PubMed Scopus (669) Google Scholar, 2Tick B. Bolton Happé F. Rutter M. Rijsdijk disorders: meta-analysis studies.J. Child Psychol. Psychiatry. 2016; 57: 585-595Crossref (441) 3Bai D. Yip B.H.K. Windham G.C. Sourander Francis Yoffe Glasson E. Mahjani Suominen Leonard et al.Association genetic environmental factors with 5-country cohort.JAMA 2019; https://doi.org/10.1001/jamapsychiatry.2019.1411Crossref (209) Scholar elucidation complex architecture revealing contributions from both common variants. Chromosomal microarray next-generation sequencing studies have many de novo inherited contribute substantially etiology ASD. It also become clear pathogenic individuals variety different defined brain including ASD, intellectual disability (ID), epilepsy, schizophrenia, other conditions.4Moreno-De-Luca Myers S.M. Challman T.D. Moreno-De-Luca Evans D.W. Ledbetter D.H. Developmental dysfunction: revival expansion old concepts new evidence.Lancet Neurol. 2013; 12: 406-414Abstract Full Text PDF (213) 5Stessman H.A. Turner T.N. Eichler E.E. Molecular subtyping improved treatment disease.Genome Med. 8: 22https://doi.org/10.1186/s13073-016-0278-zCrossref (12) 6O'Donovan M.C. Owen M.J. implications shared genetics psychiatric disorders.Nat. 22: 1214-1219Crossref (92) 7Sullivan P.F. Geschwind Defining genetic, genomic, cellular, diagnostic architectures disorders.Cell. 177: 162-183Abstract (183) 8Wang W. Corominas Lin G.N. De mutations exome From discovery application.Front. Genet. 10: 258https://doi.org/10.3389/fgene.2019.00258Crossref (33) 9Zarrei Burton C.L. Engchuan Young E.J. Higginbotham MacDonald J.R. Trost Chan A.J.S. Walker Lamoureux al.A data resource genomic copy number variation disorders.NPJ Genom. 4: 26https://doi.org/10.1038/s41525-019-0098-3Crossref (76) known collective contribution greatest disorders (NDDs) such ID, but they important etiologic conditions onset childhood (e.g., attention-deficit/hyperactivity [ADHD]) adolescence schizophrenia) and, lesser degree, later-onset mood disorders. literature reflects comment "autism genes," phenotype participants. NDD phenotypes, along current lack sufficient specificity, well possibility sources variation, variant-related polygenic risk, may ASD-specific risk. To date, no only ID NDDs. However, several attempted (ASD-predominant ASD-biased) by comparing distribution likely gene-disruptive cohorts ascertained and/or developmental delay (ID/DD).10Stessman Xiong Coe B.P. Wang T. Hoekzema K. Fenckova Kvarnung Gerdts J. Trinh Cosemans N. al.Targeted identifies 91 neurodevelopmental-disorder developmental-disability biases.Nat. 2017; 49: 515-526Crossref (310) 11Satterstrom F.K. Kosmicki J.A. Breen M.S. Rubeis An J.-Y. Peng Collins Grove Klei L. al.). Large-scale study implicates functional changes neurobiology autism.Cell. 2020; https://doi.org/10.1016/j.cell.2019.12.036Abstract (723) 12Coe Stessman H.A.F. Sulovari Geisheker M.R. Bakken T.E. Lake A.M. Dougherty J.D. Lein E.S. Hormozdiari Bernier R.A. Neurodevelopmental disease mutation morbidity.Nat. 51: 106-116Crossref (147) For example, Satterstrom al.11Satterstrom asserted among 102 some ASD-predominant, others associated more global impairment, severe (ASD ID/DD), comparison frequency disruptive (n = 11,986) those ID/DD 5,264). In study, authors "ASD-predominant genes" ratio compared was greater than 1.0. Conversely, were classified "ASD (referred here ID/DD") ASD-ascertained participants ID/DD-ascertained less manner, 50 ASD-predominant 49 ID/DD. Three additional assigned group basis case-control data, bringing total 53 genes.11Satterstrom al.12Coe ASD- did find 253 candidate excess through use two statistical models. fact, 72% predicted be significant models showed cohorts. This included fewer 5,624) colleagues,11Satterstrom similar 5,303). evaluated these overlapped almost completely; each used samples five previously studies, four accounting 99% samples.11Satterstrom 13Rauch Wieczorek Graf Wieland Endele Schwarzmayr Albrecht Bartholdi Beygo Di Donato al.Range non-syndromic sporadic disability: an study.Lancet. 2012; 380: 1674-1682Abstract (764) 14de Ligt Willemsen M.H. van Bon B.W. Kleefstra Yntema H.G. Kroes Vulto-van Silfhout A.T. Koolen D.A. Vries Gilissen C. al.Diagnostic persons disability.N. Engl. 367: 1921-1929Crossref (1130) 15Lelieveld S.H. Reijnders Pfundt Kamsteeg B.B. Löhner al.Meta-analysis 2,104 trios provides support 10 disability.Nat. Neurosci. 19: 1194-1196Crossref (269) 16Deciphering Disorders Study.Prevalence disorders.Nature. 542: 433-438Crossref (765) Although issue whether loss-of-function certain explored mainly relation question applies NDDs well. Recently, burden protein-truncating evolutionarily constrained shown ADHD.17Satterstrom Walters R.K. Singh Wigdor E.M. Lescai Demontis Stevens Bybjerg-Grauholm al.iPSYCH-Broad ConsortiumAutism attention deficit hyperactivity variants.Nat. 1961-1965Crossref (81) One analysis limited one diagnosis ADHD, both; comorbid diagnoses) confined set 212 variant Even ASD-derived gene set, rates ADHD significantly different.17Satterstrom pragmatic terms availability, problem cohort-ascertainment-based approach bias introduced unequal opportunity participant receive (i.e., ID) due uniform phenotyping studies. Because bias, phenotypic overlap groups unclear; prevalence quantified,13Rauch Scholar,18Gilissen Hehir-Kwa J.Y. Thung D.T. Vorst Kwint Janssen I.M. Hoischen Schenck al.Genome major causes disability.Nature. 511: 344-347Crossref (783) Scholar,19Halvardson Zhao J.J. Zaghlool Wentzel Georgii-Hemming Månsson Ederth Sävmarker Brandberg G. Soussi Zander Thuresson A.C. Feuk Mutations HECW2 epilepsy.J. 53: 697-704Crossref (46) minority subset participants.11Satterstrom Scholar,12Coe standardized measures frequently utilized cohorts.11Satterstrom majority came Deciphering Study, recruitment criteria phenotypes congenital anomalies, dysmorphic features, abnormal growth addition diagnoses. Differences age impact individual diagnosis. Another type scientifically arbitrary threshold define ASD-predominance (relative exomes versus exomes); cutoff >1.0 meaning simple could ASD-predominance. narrow distinction dubious clinical significance. if equally sized yielded 13 particular cases 12 cases, relative would 1.08 (13/12), met. non-overlapping diagnoses none subjects had ASD), rate 52% (13/25), 48% (12/25), certainly indication specificity. it possible scenario, all ID. case, still even though 25 (100%) poses challenge validity ascertainment-based approach. able assess intelligence quotient (IQ) differences Individuals who participate ascertainment because methods tests administered), very low IQ. someone IQ 40 characteristics 70, discrepant becausee Diagnostic Statistical Manual Mental Disorders, 5th Edition (DSM-5) specifies "to make disability, social communication should below expected general level."20American Psychiatric AssociationDiagnostic DSM-5.Fifth Edition. American Association, 2012Google degree interaction impairment what expectation 40, resulting former meeting DSM-5 latter colleagues11Satterstrom demonstrated variants, occur commonly higher (defined > 70 82 separate analyses); suggests do solely impair cognition. finding does eliminate difference mean primary factor responsible classification not. Among probands detected available full-scale (which represented 46.8% familyb ased 25.1% < 70) 30.6%, three groups: + (mean 62) 74) idiopathic 82).11Satterstrom All means population 100, cognition mutated 74), great 62).11Satterstrom Similarly, Simons Simplex Collection (SSC), (LGD) 173 high-confidence ASD-associated lower (69.1) severity 2,216; 81.9).21Jensen Smolen Girirajan Gene discoveries biased towards comorbidity disability.bioRxiv. https://doi.org/10.1101/715755Crossref (0) When subgroup 100 337) 562), LGD overall ID.21Jensen cohort, coexisting increased presence gene. evident sources. Geisinger Brain Disorder Genes Database (DBD Database) integrates genome sequencing, array, targeted six (including examine (pLoF) (see Web Resources).22Gonzalez-Mantilla A.J. Martin A cross-disorder method novel disorders.JAMA 73: 275-283Crossref (72) At time accessed, database 5,031 553 information 923 unique articles March 2003 2019 met curation criteria.22Gonzalez-Mantilla 59 at least pLOF database, exclusively (Figure 1). CHD8 [MIM: 610528], SHANK3 606230], SCN2A 182390], only, without (ID 68%, 52%, 62% CHD8, SHANK3, SCN2A, respectively). variability therefore subject bias. Detailed another source evaluating discussed model gene" ASD.23Bernier Golzio Penn O. Witherspoon Baker al.Disruptive subtype early development.Cell. 158: 263-276Abstract (469) 89 whom available, (62/89, 70%) suggested DBD query (Bernier, unpublished data). Specific scores individuals: nonverbal 67.8 (SD 28.6) 40) verbal 65.5 28.2) 35). Douzgou colleagues reported 17 (68%) (81% 21 about functioning).24Douzgou Liang H.W. Metcalfe Somarathi Tischkowitz Mohamed Kini U. McKee Yates Bertoli al.Deciphering StudyThe presentation caused truncating variants.Clin. 96: 72-84Crossref (19) Twenty-one (84%) ASD.24Douzgou concern mild identified. Guo al. 25Guo Wu Long Li Xun Ou Chen D

Language: Английский

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Differences between germline genomes of monozygotic twins

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(1), P. 27 - 34

Published: Jan. 1, 2021

Language: Английский

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The role of GABAergic signalling in neurodevelopmental disorders

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 22(5), P. 290 - 307

Published: March 26, 2021

Language: Английский

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