L'élévation du numéro de copie des gènes 22q11.2 arrête la maturation développementale de la capacité de la mémoire de travail et la neurogenèse de l'hippocampe chez les adultes

Aperçu: G.M.

La capacité de mémoire de travail, une composante essentielle de la fonction exécutive, s'élargit développementalement depuis l'enfance jusqu'à l'âge adulte. Des anomalies dans ce processus de développement sont observées chez les personnes avec un diagnostic de "trouble du spectre de l'autisme (TSA), dans la schizophrénie et les déficiences intellectuelles (DI), impliquant ce processus atypique dans la trajectoire des troubles neuropsychiatriques du développement.  

Cependant, les substrats cellulaires et neuronaux sous-jacents à ce processus ne sont pas compris. La duplication et la triplication de la variation du nombre de copies de 22q11.2 sont associées de façon constante et solide aux déficits cognitifs du TSA et de la DI chez les humains, et la surexpression des petits segments 22q11.2 récapitule les aspects dimensionnels des troubles neuropsychiatriques du développement chez la souris.  

En utilisant une approche d'expression génique sélective par type de région et de cellule, les chercheurs ont démontré que les élévations des nombres de copies de deux gènes (COMT, Tbx1), codés dans les deux petits segments 22q11.2 dans l'hippocampe, empêche la maturation du développement de la capacité de mémoire de travail chez la souris. 

Ces données fournissent une preuve de l'hypothèse nouvelle selon laquelle les élévations des nombres de copies de ces gènes 22q11.2 modifient la trajectoire développementale de la capacité de la mémoire de travail via une neurogénèse adulte sous-optimale dans l'hippocampe.

Mol Psychiatry. 2017 Aug 22. doi: 10.1038/mp.2017.158.

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis

Boku S¹, Izumi T^1,2, Abe S¹, Takahashi T¹, Nishi A¹, Nomaru H¹, Naka Y¹, Kang G¹, Nagashima M¹, Hishimoto A¹, Enomoto S¹, Duran-Torres G³, Tanigaki K⁴, Zhang J⁵, Ye K⁶, Kato S⁷, Männistö PT³, Kobayashi K⁷, Hiroi N^1,8,9.

Author information

1

Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.

2

Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

3

Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.

4

Research Institute, Shiga Medical Center, Moriyama-shi, Shiga, Japan.

5

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.

6

Department of Epidemiology &Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

7

Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.

8

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.

9

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Abstract

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.Molecular Psychiatry advance online publication, 22 August 2017; doi:10.1038/mp.2017.158.

PMID:28827761

DOI:10.1038/mp.2017.158

L'aptitude à la reproduction et le risque génétique de troubles psychiatriques dans la population générale

Aperçu: G.M.

La persistance de troubles psychiatriques communs et héréditaires qui réduisent la forme physique reproductive est un paradoxe évolutif. Ici, nous étudions les pressions de sélection sur les variantes de séquence qui prédisposent à la schizophrénie, l'autisme, le trouble bipolaire, la dépression majeure et le trouble déficitaire de l'attention avec hyperactivité (TDAH) en utilisant des données génomiques provenant de 150 656 Islandais, à l'exclusion de ceux qui ont été diagnostiqué pour ces "maladies psychiatriques"

Le risque polygénique d'autisme et de TDAH est associé au nombre d'enfants. Le risque polygénique plus élevé d'autisme est associé à moins d'enfants et un âge avancé au premier enfant alors que le risque plus élevé de polygénie du TDAH est associé à avoir plus d'enfants.  

Nous ne trouvons aucune preuve d'un avantage sélectif d'un risque polygénique élevé de schizophrénie ou de trouble bipolaire. 

 Les variations du nombre de copies rares conférant un risque modéré à élevé de maladie psychiatrique sont associées à "avoir moins d'enfants" et sont soumises à une pression de sélection négative plus forte que les variantes de séquence communes.

Nat Commun. 2017 Jun 13;8:15833. doi: 10.1038/ncomms15833.

Reproductive fitness and genetic risk of psychiatric disorders in the general population

Mullins N^1,2, Ingason A¹, Porter H^1,2, Euesden J^1,2,3, Gillett A^1,2, Ólafsson S^1,4, Gudbjartsson DF¹, Lewis CM^1,2,5, Sigurdsson E^4,6, Saemundsen E⁷, Gudmundsson ÓÓ¹, Frigge ML¹, Kong A¹, Helgason A^1,8, Walters GB^1,4, Gustafsson O¹, Stefansson H¹, Stefansson K^1,4.

Author information

1

deCODE genetics, 101 Reykjavik, Iceland.

2

MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.

3

Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2EG, UK.

4

Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.

5

Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.

6

Department of Psychiatry, Landspitali University Hospital, 101 Reykjavik, Iceland.

7

The State Diagnostic and Counselling Centre, 200 Kópavogur, Iceland.

8

Department of Anthropology, University of Iceland, 101 Reykjavik, Iceland.

Abstract

The persistence of common, heritable psychiatric disorders that reduce reproductive fitness is an evolutionary paradox. Here, we investigate the selection pressures on sequence variants that predispose to schizophrenia, autism, bipolar disorder, major depression and attention deficit hyperactivity disorder (ADHD) using genomic data from 150,656 Icelanders, excluding those diagnosed with these psychiatric diseases. Polygenic risk of autism and ADHD is associated with number of children. Higher polygenic risk of autism is associated with fewer children and older age at first child whereas higher polygenic risk of ADHD is associated with having more children. We find no evidence for a selective advantage of a high polygenic risk of schizophrenia or bipolar disorder. Rare copy-number variants conferring moderate to high risk of psychiatric illness are associated with having fewer children and are under stronger negative selection pressure than common sequence variants.

PMID:28607503

DOI:10.1038/ncomms15833

Puce à ADN pour le diagnostic clinique: une étude de 337 patients avec anomalies congénitales et retards de développement ou déficience intellectuelle

Aperçu: G.M.

L'objectif de l'étude était de déterminer le rendement diagnostique et les critères qui pourraient aider à classer et à interpréter les variations de nombre de copies (CNV) détectées par la technique de la puce à ADN (CMA) chez les patients avec anomalies congénitales et développementales, comprenant la dysmorphie, le retard de développement (DD) ou le handicap intellectuel (ID) , les troubles du spectre de l'autisme (TSA) et les anomalies congénitales (CA).

La puce à ADN a été utile pour établir le diagnostic chez une forte proportion de patients. Les critères de classification et d'interprétation des CNV comprennent la taille et le type de la CNV, le mode d'héritage et la corrélation génotype-phénotype. 

Croat Med J. 2017 Jun 14;58(3):231-238.

Chromosomal microarray in clinical diagnosis: a study of 337 patients with congenital anomalies and developmental delays or intellectual disability

Sansović I¹, Ivankov AM, Bobinec A, Kero M, Barišić I.

Author information

1

Ivona Sansović, Department of Medical Genetics and Reproductive Health, Children's Hospital Zagreb, Klaićeva 16, 10000 Zagreb, Croatia, ivonas3010@gmail.com.

Abstract

AIM:

To determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA).

METHOD:

CMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods.

RESULTS:

In 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was <300 kb (40.5%). Deletions and de novo imbalances were more frequent in pathogenic CNV than in VOUS category. CMA had a high diagnostic yield of 43/307, excluding patients previously detected by other methods.

CONCLUSION:

CMA was valuable in establishing the diagnosis in a high proportion of patients. Criteria for classification and interpretation of CNVs include CNV size and type, mode of inheritance, and genotype-phenotype correlation. Agilent ISCA v2 Human Genome 8x60 K oligonucleotide microarray format proved to be reasonable resolution for clinical use, particularly in the regions that are recommended by the International Standard Cytogenomic Array (ISCA) Consortium and associated with well-established syndromes.

PMID:28613040

La délimitation moléculaire et clinique du syndrome de microdeletion 2p15p16.1

Aperçu: G.M.

La micro-délétion interstitielle 2p15p16.1 est un syndrome chromosomique rare signalé précédemment chez 33 patients. Il se caractérise par une déficience intellectuelle, un retard de développement, des "troubles du spectre de l'autisme", une microcéphalie, une faible taille, des caractéristiques dysmorphiques et de multiples défauts d'organes congénitaux. Il est défini comme un syndrome du gène contigu et deux régions critiques ont été proposées , les loci 2p15 et 2p16.1. Néanmoins, les patients avec délétion des deux régions critiques ont partagé des caractéristiques similaires du phénotype et la corarélation génotype-phénotype n'est toujours pas clair.  

Les chercheurs examinent tous les cas publiés et décrivent trois patients supplémentaires, afin de définir plus précisément la corrélation phénotype-génotype. Ils discutent ensuite de la contribution des gènes inclus dans la suppression du phénotype anormal. les trois nouveaux patients comparativement à des cas précédents ont mis en évidence que malgré deux régions critiques, la suppression distale à 2p16.1 et la suppression proximale à 2p15 sont associées à des phénotypes très proches les uns des autres.

Am J Med Genet A. 2017 Jun 1. doi: 10.1002/ajmg.a.38302.

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

Lévy J^1,2, Coussement A³, Dupont C¹, Guimiot F^2,4, Baumann C¹, Viot G³, Passemard S^1,2, Capri Y¹, Drunat S¹, Verloes A¹, Pipiras E^1,2,5, Benzacken B^1,2,5, Dupont JM³, Tabet AC^1,6.

Author information

1

Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.

2

INSERM UMR1141, Paris Diderot University, AP-HP, Robert-Debré Hospital, Paris, France.

3

Cytogenetics Laboratory, APHP, Cochin Hospital, Paris Descartes University, Paris, France.

4

Department of Developmental Biology, APHP Robert-Debré hospital, Paris Diderot University, Sorbonne Paris Cité, Paris, France.

5

University Hospital Jean-Verdier, Department of Cytogenetic, Embryology and Histology, Bondy, France.

6

Neuroscience Department, Génétique Humaine et Fonction Cognitive Unit, Pasteur Institute, Paris, France.

Abstract

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

© 2017 Wiley Periodicals, Inc.

PMID: 28573701

DOI: 10.1002/ajmg.a.38302

Les variantions du nombre de copies induisent indépendamment le trouble du spectre de l'autisme

Aperçu: G.M.

L'examen de la variation du nombre de copies (CNV) est essentiel pour comprendre l'étiologie des troubles du spectre de l'autisme liés à la CNV (TSA). Des échantillons d'ADN ont été obtenus auprès de 64 probants  avec TSA, qui ont été génotypés sur une plate-forme Affymetrix CytoScan HD.

Au total, 29 CNV, en chevauchement avec 520 gènes, dont 315 gènes OMIM, ont été identifiés. 

En outre, MEF2C avec deux cas de chevauchement de la CNV ont également été identifiés. 

L'analyse d'enrichissement a montré que les 520 gènes sont probablement liés aux composants de la membrane avec des fonctions de liaison aux protéines impliquées dans les processus métaboliques.  

Dans le réseau d'interaction de ces gènes, les gènes TSA connus tiennent principalement une place centrale et les gènes significatifs trouvés dans nos échantillons sont étroitement liés aux gènes TSA  connus. 

Les CNV devraient être un facteur indépendant pour induire l'autisme. Avec la stratégie de notre étude, nous pourrions trouver les gènes candidats aux TSA par les données de la CNV et examiner une certaine pathogenèse de ce trouble. 

Ces CNV ont été associés à un TSA et ils peuvent contribuer au TSA en affectant les gènes liés aux TSA. 

Biosci Rep. 2017 May 22. pii: BSR20160570. doi: 10.1042/BSR20160570.

Copy Number Variations independently induce Autism Spectrum Disorder

Xie Y¹, Yuan H², Wang M³, Zhong L⁴, Zhou J⁵, Song B⁶, Yin Q⁷, Sun X⁸.

Author information

1

Key Laboratory for Major Obstetric Diseases of Guangdong Province Guagnzhou, N/A, China fairyfareyj@sina.com.cn.

2

Guangzhou Kingmed center for clinical laboratory Co., Ltd, Guangzhou 510330, Guangdong, PR China, Guanzhou, N/A, China.

3

Shenzhen Following Precision Medical Research Institute, Shenzhen, Guangdong, China, N/A, China.

4

Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, N/A, China.

5

Division of psychology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China;, Shenzhen, China.

6

Key Laboratory for Major Obstetric Diseases of Guangdong Province Guagnzhou, N/A, China.

7

Yucai School, Shenyang 110179，Liaoning, China, Liaoling, N/A, China.

8

Key Laboratory for Major Obstetric Diseases of Guangdong Province Guangzhou, China.

Abstract

The examination of copy number variation (CNV) is critical to understanding the etiology of the CNV-related autism spectrum disorders (ASD). DNA samples were obtained from 64 ASD probands, which were genotyped on an Affymetrix CytoScan HD platform. qPCR or FISH were used as a validation for some novel recurrent CNVs. We further compared the clinical phenotypes of the genes in the DECIPHER database with these overlapping genes.  Using vast, readily available databases with previously reported clinically relevant CNVs from human populations, the genes were evaluated using Enrichment Analysis and GO Slim Classification. By using the Ploysearch2 software, we identified the interaction relationship between significant genes and known ASD genes.A total of 29 CNVs, overlapping with 520 genes, including 315 OMIM genes, were identified. Additionally, MEF2C with two cases of CNV overlap were also identified. Enrichment analysis showed that the 520 genes are most likely related to membrane components with protein binding functions involved in metabolic processes. In the interaction network of those genes, the known ASD genes are mostly at the core position and the significant genes found in our samples are closely related to the known ASD genes.CNVs should be an independent factor to induce autism. With the strategy of our study, we could find the ASDs candidate genes by CNVs data and review certain pathogenesis of this disorder. Those CNVs were associated with ASD and they may contribute to ASD by affecting the ASD-related genes.

©2017 The Author(s).

PMID: 28533427

DOI: 10.1042/BSR20160570

L'effet conjugué de l'exposition à la pollution atmosphérique et la variation du nombre de copies sur le risque d'autisme.

Aperçu: G.M.

Le trouble du spectre de l'autisme est un trait complexe avec un haut degré d'héritabilité ainsi qu'une susceptibilité par des facteurs environnementaux. 

L'étude n'a mis en évidence aucune corrélation entre l'exposition moyenne à la pollution atmosphérique de la conception à l'âge de 2 ans et le fardeau de la CNV (variation du nombre de copie)  de l'enfant. 

Il a été observé une interaction significative dans laquelle une augmentation du taux de duplication associé à une augmentation de 1SD de l'exposition à l'ozone était associée à un risque élevé d'autisme beaucoup plus élevé que les risques accrus associés à la duplication génomique ou de l'ozone seul.

Autism Res. 2017 Apr 27. doi: 10.1002/aur.1799.

The joint effect of air pollution exposure and copy number variation on risk for autism

Kim D^1,2, Volk H³, Girirajan S¹, Pendergrass S², Hall MA¹, Verma SS², Schmidt RJ^4,5, Hansen RL^5,6, Ghosh D⁷, Ludena-Rodriguez Y⁴, Kim K, Ritchie MD^1,2, Hertz-Picciotto I^4,5, Selleck SB¹.

Author information

1

Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, 16802.

2

Biomedical & Translational Informatics Institute, Geisinger Health System, Danville, PA, 17822.

3

Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205.

4

Department of Public Health Sciences, University of California, Davis, Davis, CA.

5

The MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA.

6

Department of Pediatrics, Davis School of Medicine, University of California, Sacramento, CA, 95817.

7

Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045.

Abstract

Autism spectrum disorder is a complex trait with a high degree of heritability as well as documented susceptibility from environmental factors. In this study the contributions of copy number variation, exposure to air pollutants, and the interaction between the two on autism risk, were evaluated in the population-based case-control Childhood Autism Risks from Genetics and Environment (CHARGE) Study. For the current investigation, we included only those CHARGE children (a) who met criteria for autism or typical development and (b) for whom our team had conducted both genetic evaluation of copy number burden and determination of environmental air pollution exposures based on mapping addresses from the pregnancy and early childhood. This sample consisted of 158 cases of children with autism and 147 controls with typical development. Multiple logistic regression models were fit with and without environmental variable-copy number burden interactions. We found no correlation between average air pollution exposure from conception to age 2 years and the child's CNV burden. We found a significant interaction in which a 1SD increase in duplication burden combined with a 1SD increase in ozone exposure was associated with an elevated autism risk (OR 3.4, P < 0.005) much greater than the increased risks associated with either genomic duplication (OR 1.85, 95% CI 1.25-2.73) or ozone (OR 1.20, 95% CI 0.93-1.54) alone. Similar results were obtained when CNV and ozone were dichotomized to compare those in the top quartile relative to those having a smaller CNV burden and lower exposure to ozone, and when exposures were assessed separately for pregnancy, the first year of life, and the second year of life. No interactions were observed for other air pollutants, even those that demonstrated main effects; ozone tends to be negatively correlated with the other pollutants examined. While earlier work has demonstrated interactions between the presence of a pathogenic CNV and an environmental exposure [Webb et al., 2016], these findings appear to be the first indication that global copy number variation may increase susceptibility to certain environmental factors, and underscore the need to consider both genomics and environmental exposures as well as the mechanisms by which each may amplify the risks for autism associated with the other. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

© 2017 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 28448694

DOI: 10.1002/aur.1799

Trajectoires développementales des jeunes enfants avec une variation du nombre de copies 16p11.2

Aperçu: G.M.

La variation du nombre de copies à 16p11.2 est associée à des phénotypes divers, mais on sait peu de choses sur les trajectoires de développement précoces et l'apparition du phénotype.  

Les résultats fournissent des prédictions pour les trajectoires de développement de la personne, un aperçu du fonctionnement moyen des personnes avec une variation du nombre de copie 16p11.2 à un âge précoce et soulignent la nécessité d'une surveillance continue du fonctionnement social et moteur et de la symptomatologie comportementale pour améliorer la planification du traitement.

Am J Med Genet B Neuropsychiatr Genet. 2017 Mar 27. doi: 10.1002/ajmg.b.32525.

Developmental trajectories for young children with 16p11.2 copy number variation

Bernier R¹, Hudac CM¹, Chen Q², Zeng C², Wallace AS¹, Gerdts J¹, Earl R¹, Peterson J¹, Wolken A¹, Peters A¹, Hanson E^3,4, Goin-Kochel RP⁵, Kanne S⁶, Snyder LG⁷, Chung WK⁸; Simons VIP consortium.

Author information

1

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.

2

Department of Biostatistics, Columbia University, New York, New York.

3

Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts.

4

Harvard Medical School, Boston, Massachusetts.

5

Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

6

Thompson Autism Center, University of Missouri, Columbia, Missouri.

7

Simons Foundation, New York, New York.

8

Department of Pediatrics and Medicine, Columbia University, New York, New York.

Abstract

Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. © 2017 Wiley Periodicals, Inc.

© 2017 Wiley Periodicals, Inc.

PMID: 28349640

DOI: 10.1002/ajmg.b.32525

Variation du nombre de copies dans 19 familles multiplexes italiennes avec trouble du spectre de l'autisme: Importance des gènes synaptiques et d'élongation des neurites

Aperçu: G.M.

Le trouble du spectre de l'autisme (TSA) est doté d'estimations d'héritabilité impressionnantes et de taux de récidive élevés. Ses fondements génétiques sont néanmoins très hétérogènes, avec des variantes communes et rares qui contribuent à des centaines de loci différents, chacun caractérisé par des niveaux variables de pénétrance. Les familles multiplex d'un seul groupe ethnique représentent un moyen utile de réduire l'hétérogénéité et d'améliorer la charge génétique.Ces résultats fournissent des preuves supplémentaires de l'hétérogénéité génétique dans les TSA, même dans les familles multiplex appartenant à un seul groupe ethnique. Les différences dans la charge de la VCN peuvent probablement contribuer à l'hétérogénéité clinique importante observée entre frères et sœurs affectés

Am J Med Genet B Neuropsychiatr Genet. 2017 Mar 17. doi: 10.1002/ajmg.b.32537.

Copy number variation in 19 Italian multiplex families with autism spectrum disorder: Importance of synaptic and neurite elongation genes

Lintas C¹, Picinelli C², Piras IS², Sacco R¹, Brogna C¹, Persico AM^2,3.

Author information

1

Service for Neurodevelopmental Disorders and Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy.

2

Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy.

3

Unit of Child and Adolescent Neuropsychiatry, "Gaetano Martino" University Hospital, University of Messina, Messina, Italy.

Abstract

Autism Spectrum Disorder (ASD) is endowed with impressive heritability estimates and high recurrence rates. Its genetic underpinnings are nonetheless very heterogeneous, with common, and rare contributing variants located in hundreds of different loci, each characterized by variable levels of penetrance. Multiplex families from single ethnic groups represent a useful means to reduce heterogeneity and enhance genetic load. We screened 19 Italian ASD multiplex families (3 triplets and 16 duplets, total N = 41 ASD subjects), using array-CGH (Agilent 180 K). Causal or ASD-relevant CNVs were detected in 36.6% (15/41) of ASD probands, corresponding to 36.8% (7/19) multiplex families with at least one affected sibling genetically positive. However, only in less than half (3/7) of positive families, affected siblings share the same causal or ASD-relevant CNV. Even in these three families, additional potentially relevant CNVs not shared by affected sib pairs were also detected. These results provide further evidence of genetic heterogeneity in ASD even within multiplex families belonging to a single ethnic group. Differences in CNV burden may likely contribute to the substantial clinical heterogeneity observed between affected siblings. In addition, Gene Ontology enrichment analysis indicates that most potentially causal or relevant ASD genes detected in our cohort belong to nervous system-specific categories, especially involved in neurite elongation and synaptic structure/function. These findings point toward the existence of genomic instability in these families, whose underlying genetic and epigenetic mechanisms deserve further scrutiny.

© 2017 Wiley Periodicals, Inc.

PMID: 28304131

DOI: 10.1002/ajmg.b.32537

Le rendement diagnostique de l'éventail CGH chez les patients avec un trouble du spectre de l'autisme à Hong Kong

Traduction partielle: G.M.

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Clin Transl Med. 2016 Dec;5(1):18. doi: 10.1186/s40169-016-0098-1. Epub 2016 May 16.

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong

Siu WK^1,2, Lam CW³, Mak CM², Lau ET⁴, Tang MH⁴, Tang WF⁴, Poon-Mak RS⁵, Lee CC⁶, Hung SF⁶, Leung PW⁷, Kwong KL⁸, Yau EK⁹, Ng GS⁹, Fong NC⁹, Chan KY⁹.

Author information

• ¹Department of Pathology, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
• ²Kowloon West Cluster Laboratory Genetics Service, Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
• ³Department of Pathology, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China. ching-wanlam@pathology.hku.hk
• ⁴Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
• ⁵Department of Clinical Psychology, Kwai Chung Hospital, Hong Kong, China.
• ⁶Department of Psychiatry, Kwai Chung Hospital, Hong Kong, China.
• ⁷Department of Psychology, The Chinese University of Hong Kong, Hong Kong, China.
• ⁸Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, China.
• ⁹Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.

Abstract

BACKGROUND:

Les biopuces chromosomiques offre une sensibilité supérieure pour l'identification des variations du nombre de copies (CNV) submicroscopiques et il est préconisé en tant que premier test génétique de niveau pour les patients avec troubles du spectre de l'autisme (TSA). À cet égard, le rendement diagnostique de l'éventail comparatif de l'hybridation génomique comparative (CGH) pour les patients avec TSA est déterminé dans une cohorte de patients chinois à Hong Kong.
Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong.

METHODS:

A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array.

RESULTS:

We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort).

CONCLUSIONS:

Dans cette étude, un rendement diagnostique satisfaisant de l'éventail CGH a été démontré dans une cohorte  chinoise de patient avec TSA ce qui a soutenu l'utilité clinique de l'éventail CGH comme test de première ligne du TSA à Hong Kong.
In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

PMID: 27271878

PMCID: PMC4896892

DOI: 10.1186/s40169-016-0098-1