A large data resource of genomic copy number variation across neurodevelopmental disorders

Mehdi Zarrei^{1

2}, Christie L Burton³, Worrawat Engchuan^{1

2}, Edwin J Young⁴, Edward J Higginbotham^{1

2

5}, Jeffrey R MacDonald¹, Brett Trost^{1

2}, Ada J S Chan^{1

2

5}, Susan Walker¹, Sylvia Lamoureux¹, Tracy Heung⁶, Bahareh A Mojarad², Barbara Kellam¹, Tara Paton¹, Muhammad Faheem^{1

2}, Karin Miron^{1

2}, Chao Lu¹, Ting Wang¹, Kozue Samler¹, Xiaolin Wang¹, Gregory Costain^{7

8}, Ny Hoang^{2

5

9}, Giovanna Pellecchia¹, John Wei¹, Rohan V Patel¹, Bhooma Thiruvahindrapuram¹, Maian Roifman^{7

10

11}, Daniele Merico^{1

12}, Tara Goodale³, Irene Drmic¹³, Marsha Speevak¹⁴, Jennifer L Howe¹, Ryan K C Yuen^{1

2}, Janet A Buchanan¹, Jacob A S Vorstman^{15

16}, Christian R Marshall^{1

4

17}, Richard F Wintle¹, David R Rosenberg^{18

19}, Gregory L Hanna²⁰, Marc Woodbury-Smith^{1

21}, Cheryl Cytrynbaum^{2

5

7

22}, Lonnie Zwaigenbaum²³, Mayada Elsabbagh²⁴, Janine Flanagan¹¹, Bridget A Fernandez²⁵, Melissa T Carter²⁶, Peter Szatmari^{15

27

28}, Wendy Roberts¹⁶, Jason Lerch^{29

30}, Xudong Liu³¹, Rob Nicolson^{32

33}, Stelios Georgiades³⁴, Rosanna Weksberg^{2

7

5}, Paul D Arnold^{2

35

36}, Anne S Bassett^{6

15

37}, Jennifer Crosbie^{3

15}, Russell Schachar^{3

15

38}, Dimitri J Stavropoulos⁴, Evdokia Anagnostou³⁹, Stephen W Scherer^{1

2

5

40}

Affiliations

¹ 1The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON Canada.
² 2Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
³ 3Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON Canada.
⁴ 4Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON Canada.
⁵ 5Department of Molecular Genetics, University of Toronto, Toronto, ON Canada.
⁶ 6Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON Canada.
⁷ 7Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON Canada.
⁸ 8Medical Genetics Residency Training Program, University of Toronto, Toronto, ON Canada.
⁹ 9Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON Canada.
¹⁰ 10The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON Canada.
¹¹ 11Department of Paediatrics, University of Toronto, Toronto, ON Canada.
¹² Deep Genomics Inc., Toronto, ON Canada.
¹³ Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.
¹⁴ 14Trillium Health Partners Credit Valley Site, Mississauga, Ontario Canada.
¹⁵ 15Department of Psychiatry, University of Toronto, Toronto, ON Canada.
¹⁶ 16Autism Research Unit, The Hospital for Sick Children, Toronto, ON Canada.
¹⁷ 17Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.
¹⁸ 18Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI USA.
¹⁹ 19The Children's Hospital of Michigan, Detroit, MI United States.
²⁰ 20Department of Psychiatry, University of Michigan, Ann Arbor, MI USA.
²¹ 21Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
²² 22Dalla Lana School of Public Health and the Department of Family and Community Medicine, University of Toronto, Toronto, ON Canada.
²³ 23Department of Pediatrics, University of Alberta, Edmonton, AB Canada.
²⁴ 24Montreal Neurological Institute, McGill University, Montreal, QC Canada.
²⁵ 25Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL Canada.
²⁶ 26Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, ON Canada.
²⁷ 27Centre for Addiction and Mental Health, Toronto, ON Canada.
²⁸ 28Department of Psychiatry, The Hospital for Sick Children, Toronto, ON Canada.
²⁹ 29Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON Canada.
³⁰ 30Department of Medical Biophysics, The University of Toronto, Toronto, ON Canada.
³¹ 31Department of Psychiatry, Queen's University, Kinston, ON Canada.
³² 32Children's Health Research Institute, London, ON Canada.
³³ 33Western University, London, ON Canada.
³⁴ 34Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON Canada.
³⁵ 35Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB Canada.
³⁶ 36Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
³⁷ 37The Dalglish Family 22q Clinic, Toronto General Hospital, Toronto, ON Canada.
³⁸ 38Institute of Medical Science, University of Toronto, Toronto, ON Canada.
³⁹ 39Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, ON Canada.
⁴⁰ 40Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON Canada.

PMID: 31602316
PMCID: PMC6779875
DOI: 10.1038/s41525-019-0098-3

A large data resource of genomic copy number variation across neurodevelopmental disorders

Mehdi Zarrei et al. NPJ Genom Med. 2019.

. 2019 Oct 7:4:26.

doi: 10.1038/s41525-019-0098-3. eCollection 2019.

Authors

Affiliations

¹ 1The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON Canada.
² 2Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
³ 3Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON Canada.
⁴ 4Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON Canada.
⁵ 5Department of Molecular Genetics, University of Toronto, Toronto, ON Canada.
⁶ 6Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON Canada.
⁷ 7Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON Canada.
⁸ 8Medical Genetics Residency Training Program, University of Toronto, Toronto, ON Canada.
⁹ 9Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON Canada.
¹⁰ 10The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON Canada.
¹¹ 11Department of Paediatrics, University of Toronto, Toronto, ON Canada.
¹² Deep Genomics Inc., Toronto, ON Canada.
¹³ Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.
¹⁴ 14Trillium Health Partners Credit Valley Site, Mississauga, Ontario Canada.
¹⁵ 15Department of Psychiatry, University of Toronto, Toronto, ON Canada.
¹⁶ 16Autism Research Unit, The Hospital for Sick Children, Toronto, ON Canada.
¹⁷ 17Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.
¹⁸ 18Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI USA.
¹⁹ 19The Children's Hospital of Michigan, Detroit, MI United States.
²⁰ 20Department of Psychiatry, University of Michigan, Ann Arbor, MI USA.
²¹ 21Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
²² 22Dalla Lana School of Public Health and the Department of Family and Community Medicine, University of Toronto, Toronto, ON Canada.
²³ 23Department of Pediatrics, University of Alberta, Edmonton, AB Canada.
²⁴ 24Montreal Neurological Institute, McGill University, Montreal, QC Canada.
²⁵ 25Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL Canada.
²⁶ 26Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, ON Canada.
²⁷ 27Centre for Addiction and Mental Health, Toronto, ON Canada.
²⁸ 28Department of Psychiatry, The Hospital for Sick Children, Toronto, ON Canada.
²⁹ 29Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON Canada.
³⁰ 30Department of Medical Biophysics, The University of Toronto, Toronto, ON Canada.
³¹ 31Department of Psychiatry, Queen's University, Kinston, ON Canada.
³² 32Children's Health Research Institute, London, ON Canada.
³³ 33Western University, London, ON Canada.
³⁴ 34Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON Canada.
³⁵ 35Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB Canada.
³⁶ 36Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
³⁷ 37The Dalglish Family 22q Clinic, Toronto General Hospital, Toronto, ON Canada.
³⁸ 38Institute of Medical Science, University of Toronto, Toronto, ON Canada.
³⁹ 39Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, ON Canada.
⁴⁰ 40Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON Canada.

PMID: 31602316
PMCID: PMC6779875
DOI: 10.1038/s41525-019-0098-3

Abstract

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

Keywords: Molecular medicine; Neurodevelopmental disorders; Pathogenesis.

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Conflict of interest statement

Competing interestsS.W.S. serves on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property originating from his research and held at the Hospital for Sick Children is licensed to Lineagen, and separately Athena Diagnostics. D.M. is a full-time employee of Deep Genomics and is entitled to a stock option. R.J.S., P.D.A., and J.C. consult for Highland Therapeutics. Intellectual property from ADHD research at the Hospital for Sick Children is licensed to Ehave and the National Research Council of Canada. Other authors declare no competing interests for the data and interpretation presented in this study. R.J.S., P.D.A., and J.C. consults for Highland Therapeutics. Intellectual property from their research at the Hospital for Sick Children is licensed to Ehave and the National Research Council. D.M. is a full-time employee of Deep Genomics and is entitled to stock options. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately to Lineagen. These relationships did not influence data interpretation or presentation during this study, but are disclosed for potential future consideration.

Figures

**Fig. 1**
Distribution of a) aneuploidies and b) known recurrent genomic disorder CNVs found in cases diagnosed with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), or obsessive compulsive disorder (OCD). Details of the copy number variants, sex, and variant sizes are in Table 1, Supplementary Table 1A. *DEL* deletion, *DUP* duplication, *TAR* Thrombocytopenia-Absent Radius syndrome locus, *STS* includes STS, BP breakpoint, *LCR* low-copy repeat, *Prox* proximal, *Dist* distal

**Fig. 2**
Genes impacted by rare CNVs in more than one case. a) brain-expressed and moderately constrained genes (pLI > 0.45) impacted by deletions in multiple cases, b) brain-expressed genes with duplication of their full-length transcript in more than one case

See this image and copyright information in PMC

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A large data resource of genomic copy number variation across neurodevelopmental disorders

Affiliations

A large data resource of genomic copy number variation across neurodevelopmental disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

Miscellaneous