A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

被引：59

作者：

Chawner, Samuel J. R. A. ^{[1
,2
]}

Doherty, Joanne L. ^{[1
]}

Anney, Richard J. L. ^{[1
]}

Antshel, Kevin M. ^{[3
]}

Bearden, Carrie E. ^{[4
]}

Bernier, Raphael ^{[5
,6
]}

Chung, Wendy K. ^{[7
,8
]}

Clements, Caitlin C. ^{[9
,10
]}

Curran, Sarah R. ^{[11
]}

Cuturilo, Goran ^{[12
,13
]}

Fiksinski, Ania M. ^{[14
,15
,16
]}

Gallagher, Louise ^{[17
]}

Goin-Kochel, Robin P. ^{[18
]}

Gur, Raquel E. ^{[19
,20
,21
,22
]}

Hanson, Ellen ^{[23
]}

Jacquemont, Sebastien ^{[24
,25
]}

Kates, Wendy R. ^{[26
]}

Kushan, Leila ^{[4
]}

Maillard, Anne M. ^{[24
,27
]}

McDonald-McGinn, Donna M. ^{[28
,29
,30
]}

Mihaljevic, Marina ^{[31
]}

Miller, Judith S. ^{[9
]}

Moss, Hayley ^{[1
]}

Pejovic-Milovancevic, Milica ^{[13
,32
]}

Schultz, Robert T. ^{[9
,22
,30
]}

Green-Snyder, Leeanne ^{[33
]}

Vorstman, Jacob A. ^{[14
,34
,35
]}

Wenger, Tara L. ^{[36
]}

Hall, Jeremy ^{[1
,37
]}

Owen, Michael J. ^{[1
,37
]}

van den Bree, Marianne B. M. ^{[1
,37
]}

机构：

[1] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Div Psychol Med & Clin Neurosci, Cardiff, Wales

[2] Cardiff Univ, Ctr Human Dev Sci, Sch Psychol, Cardiff, Wales

[3] Syracuse Univ, Dept Psychol, Syracuse, NY USA

[4] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat & Behav Sci & Psychol, Los Angeles, CA 90024 USA

[5] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA

[6] Univ Washington, Dept Behav Sci, Seattle, WA 98195 USA

[7] Columbia Univ, Dept Pediat, Irving Med Ctr, New York, NY 10027 USA

[8] Columbia Univ, Dept Med, Irving Med Ctr, New York, NY 10027 USA

[9] Univ Penn, Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA

[10] Univ Penn, Dept Psychol, 3815 Walnut St, Philadelphia, PA 19104 USA

[11] South West London & St Georges Mental Hlth Natl H, London, England

[12] Univ Childrens Hosp, Belgrade, Serbia

[13] Univ Belgrade, Fac Med, Belgrade, Serbia

[14] Univ Med Ctr Utrecht, Brain Ctr, Dept Psychiat, Utrecht, Netherlands

[15] Univ Hlth Network, Toronto Gen Hosp, Clin Genet Res Program, Ctr Addict & Mental Hlth, Toronto, ON, Canada

[16] Univ Hlth Network, Toronto Gen Hosp, Dalglish Family Clin Delet Syndrome 22q 22G11 2, Toronto, ON, Canada

[17] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland

[18] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[19] Univ Penn, Childrens Hosp Philadelphia, Lifespan Brain Inst, Philadelphia, PA 19104 USA

[20] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[21] Univ Penn, Dept Psychiat, Neurodev & Psychosis Sect, Perelman Sch Med, Philadelphia, PA 19104 USA

[22] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat, Philadelphia, PA 19104 USA

[23] Harvard Med Sch, Childrens Hosp Boston, Dev Med, Boston, MA 02115 USA

[24] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[25] Ctr Hosp Univ St Justine, Ctr Rech, Montreal, PQ, Canada

[26] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA

[27] Lausanne Univ Hosp, Serv Troubles Spectre Autisme & Apparentes, Lausanne, Switzerland

[28] Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA

[29] Childrens Hosp Philadelphia, 22q & You Ctr, Philadelphia, PA 19104 USA

[30] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA

[31] Univ Belgrade, Fac Med, Clin Ctr Serbia, Clin Psychiat, Belgrade, Serbia

[32] Inst Mental Hlth, Belgrade, Serbia

[33] Simons Fdn, New York, NY USA

[34] SickKids Res Inst, Program Genet & Genome Biol, Toronto, ON, Canada

[35] Univ Toronto, Hosp Sick Children, Dept Psychiat, Toronto, ON, Canada

[36] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA

[37] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff, Wales

来源：

AMERICAN JOURNAL OF PSYCHIATRY | 2021年 / 178卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会; 瑞士国家科学基金会;

关键词：

22Q11.2 DELETION SYNDROME; SPECTRUM DISORDERS; SPECIAL NEEDS; DE-NOVO; CHILDREN; INDIVIDUALS; PREVALENCE; CNVS; INTELLIGENCE; BEHAVIOR;

D O I：

10.1176/appi.ajp.2020.20010015

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcomein individual genetic variant groups(74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

引用

页码：77 / 86

页数：10

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