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Lowther et al.
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SUPPLEMENTARY MATERIAL
Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases
identifies exons important for neurodevelopmental disease expression
Chelsea Lowther, BSc1, Marsha Speevak, PhD2, Christine M. Armour, MD, MSc3, Elaine S.
Goh, MD2, Gail E. Graham, MD4, Chumei Li, MD, PhD4,5, Susan Zeesman, MSc5, Malgorzata
J.M. Nowaczyk, MD5,6, Lee-Anne Schultz, MSc5, Antonella Morra, MD2, Rob Nicolson, MD7,
Peter Bikangaga, MD8, Dawa Samdup, MD9, Mostafa Zaazou, MD2, Kerry Boyd, MD10, Jack H.
Jung, MD11, Victoria Siu, MD12, Manjulata Rajguru, MD13, Sharan Goobie, MD12, Mark A.
Tarnopolsky, MD14, Chitra Prasad, MD12, Paul T. Dick, MD15, Asmaa S. Hussain, MD11,
Margreet Walinga, MD16, Renske G. Reijenga, MD17, Matthew Gazzellone, MSc18, Anath C.
Lionel, PhD18, Christian R. Marshall, PhD18, Stephen W. Scherer, PhD18,19, Dimitri J.
Stavropoulos, PhD20, Elizabeth McCready, PhD6, Anne S. Bassett, MD1,21
Supplementary Material
Table S1. Clinical checklist
Page
2-5
Table S2. Summary of demographic and clinical characteristics of
probands with rare deletions overlapping NRXN1 identified by
clinical microarray
6
Table S3. Control datasets examined for exonic and intronic NRXN1
deletions
7
Table S4. Number of NRXN1 deletions found in each Canadian
laboratory
8
Table S5. Control dataset acknowledgements
9
References
10
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Table S1. Clinical checklist
Laboratory ID: __________________________ Age at last assessment: _
Patient’s sex:
M
F
__
Month/Year of birth: _____
Growth parameters at last assessment: Ht (cm):
(cm):_____
Wt (kg):
Head circumference
Reason for undergoing microarray testing (check all that apply):
 Developmental delay
 Intellectual disability
 Autism spectrum
disorder
 Congenital malformation(s)
 Dysmorphic features
 Growth abnormalities
Other (please specify):
____________________________________________________________
Clinical Checklist
Absent
or none
(check)
Unsure
or not
assessed
(check)
Present (please describe)
Dysmorphic features
Relevant perinatal history
Preterm delivery – GA: ___________
Birth weight/length
Teratogen exposure
Twin pregnancy
IVF/ICSI
Other:
Congenital anomalies
Specify:
Growth abnormalities
Type (circle any that apply)
IUGR, FTT, short stature, tall stature,
obesity, overgrowth, macrocephaly,
microcephaly
Lowther et al.
Development/Cognitive functioning
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Type (circle any that apply)
Global developmental delay
Isolated speech delay
Isolated motor delay
Intellectual disability
Mild Mod Severe Profound
Psychiatric/behavioral disorder
Type (circle any that apply)
ADHD
Autism spectrum disorder
Mood disorder
Anxiety disorder
Schizophrenia
Other:
Vision problems
Type (circle any that apply)
myopia, hyperopia, strabismus,
amblyopia, cataracts, retinopathy
Other:
Hearing impairment
Type (circle any that apply)
Conductive
Sensorineural
Mixed
Other:
Seizures/epilepsy
Severity: mild mod severe profound
Type (circle any that apply)
Grand mal/GTC
Petit mal/absence
Focal/Partial complex
Myoclonic
Febrile
Infantile spasms
Age at onset:
Other:
Lowther et al.
Other neurologic features
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Type (circle any that apply)
Hypotonia
Hypertonia
Ataxia
Tremor
Nystagmus
Other:
Brain imaging abnormalities
Describe:
Musculoskeletal features
Type (circle any that apply)
Hypermobility
Scoliosis
Vertebral anomalies
Contractures
Other:
Skin/hair/dental features
Type (circle any that apply)
Hyperpigmented
Hypopigmented
Vascular lesions
Alopecia
Dental crowding
Other:
Other clinical features of note
(Eg. general health concerns, history of surgery,
unusual behaviors, etc)
Family History
Describe:
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Molecular data:
1. NRXN1 deletion coordinates: start:
stop:
size:
2. Microarray/genome build:
3. Is the NRXN1 deletion inherited?
 Yes: mat/pat
 No (de novo)  Unsure/not done
4. If yes, any clinically significant phenotype in parent?  Yes
 No
 Unsure
If yes, please specify:
5. Are parents consanguineous?  No
 Yes
 Unsure
6. Were there other CNVs on microarray analysis for this patient?
Unsure
 No
 Yes

If yes, please specify (include clinical interpretation):
7. Has any other genetic testing been done on this patient?
 No
 Yes
 Unsure
If yes, please specify tests and results:
Footnote: Similar to previous studies,1,2 DD/ID was broadly defined to include the spectrum of
ID severity (e.g., borderline to severe), a history of learning difficulties or unspecified cognitive
deficits. Macrocephaly and tall stature, and microcephaly and short stature, were defined as
physical measurements ≥90th and ≤10th percentile, respectively, assessed using sex-matched head
circumference charts that correct for height3,4 and height-for-age data tables from the Centers for
Disease Control and Prevention (http://www.cdc.gov/growthcharts). Prematurity and
postmaturity were defined as delivery at <37 and >41 weeks, respectively.5 Large for gestational
age (LGA; ≥90th percentile) and small for gestational age (SGA; ≤10th percentile) were
determined using Canadian population-based references.6
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Table S2. Summary of demographic and clinical characteristics of probands with rare
deletions overlapping NRXN1 identified by clinical microarray
Clinical feature: n (%)
Sex, male:
Age, children:
DD/ID
ASD
Speech
ADHD
Other psychiatric conditions
Anxiety
Psychotic disorder
OCD
Behavioural problems
Epilepsy/seizures
Congenital anomalies
Neuromuscular
Motor abnormalities
Congenital anomalies
Vision problems
Hearing problems
Exonic NRXN1 deletion
cases (n=44)
28 (63.6%)
35 (79.5%)
44 (100.0%)
14 (31.8%)
12 (27.3%)
4
(9.1%)
Intronic NRXN1 deletion
cases (n=19)
8 (42.1%)
17 (89.5%)
15 (78.9%)
2 (10.5%)
1 (5.3%)
-
3
2
2
5
6
4
12
4
4
5
3
1 (5.3%)
5 (26.3%)
5 (26.3%)
-
(6.8%)
(4.5%)
(4.5%)
(11.4%)
(13.6%)
(9.1%)
(27.3%)
(9.1%)
(9.1%)
(11.4%)
(6.8%)
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Table S3. Control datasets examined for exonic and intronic NRXN1 deletions
Control dataset
# individuals
Array type
Description of dataset
# of exonic NRXN1
deletions
# of intronic NRXN1
deletions
Wellcome Trust Case Control
Consortium (WTCCC) controls
4,826
Illumina 1M
Rucker et al. 2012
(Mol Psychiatry)
3
12
SAGE consortium controls
1,708
Illumina 1M
Bierut et al. 2010
(PNAS)
0
7
Health, Aging, and Body
Composition (Health ABC) study
controls
2,566
Illumina 1M Duo
Coviello et al. 2012
(PLoS Genet)
1
8
Ontario Population Genomics
Platform (OPGP) controls
873
CytoScan HD
Uddin et al. 2014
(Genet Med)
0
2
POPGEN
1,123
Affymetrix 6.0
Krawczak et al. 2006
(Community Genet)
0
0
Ottawa Heart Institute controls
1,211
Affymetrix 6,0
Stewart et al. 2009 (J
Am Coll Cardiology)
0
9
Collaborative Genetic Study of
Nicotine Dependence (COGEND)
controls
1,182
Illumina OMNI 2.5M
Quad
Bierut et al. 2007
(HMG)
0
5
KORA controls
1,775
Illumina OMNI 2.5
Quad
Verhoeven et al. 2013
(Nature Genetics)
0
12
TOTAL
15,264
4 exonic deletions
55 intronic deletions
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Table S4. Number of NRXN1 deletions found in each Canadian laboratory
Laboratory site
Number of exonic
NRXN1 deletions
identified
Credit Valley Hospital
20
Total number of
cases submitted for
clinical microarray
6,022
Prevalence of exonic
NRXN1 deletions
0.33212
Hamilton Health
Sciences
4
1,514
0.26420
Hospital for Sick
Children
17
11,727
0.14496
TOTAL
41
19,263
0.21284
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Table S5. Control Acknowledgements
Control datasets were obtained, along with permission for use, from the database of Genotypes
and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through accession numbers
phs000143.v1.p1 (Starr County Health Studies’ Genetics of Diabetes Study), phs000091.v2.p1
(GENEVA NHS/HPFS Diabetes study), phs000169.v1.p1 (Whole Genome Association Study of
Visceral Adiposity in the HABC Study), phs000303.v1.p1 (Genetic Epidemiology of Refractive
Error in the KORA Study) and phs000404.v1.p1 (COGEND; The Genetic Architecture of
Smoking and Smoking Cessation). The Starr County Health Studies Genetics of Diabetes Study
was supported by the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the NIDDK Central Repositories. Support for the GWAS of Gene and
Environment Initiatives in Type 2 Diabetes was provided through the NIH Genes, Environment
and Health Initiative [GEI] (U01HG004399). The human subjects participating in the GWAS
derive from The Nurses’ Health Study and Health Professionals’ Follow-up Study and these
studies are supported by National Institutes of Health (NIH) grants CA87969, CA55075 and
DK58845. Assistance with phenotype harmonization and genotype cleaning, as well as with
general study coordination, was provided by the Gene Environment Association Studies,
GENEVA Coordinating Center (U01 HG004446) and the National Center for Biotechnology
Information. Support for genotyping, which was performed at the Broad Institute of MIT and
Harvard, was provided by the NIH GEI (U01HG004424). Support for the ‘CIDR Visceral
Adiposity Study’ was provided through the Division of Aging Biology and the Division of
Geriatrics and Clinical Gerontology, National Institute on Aging. Assistance with phenotype
harmonization and genotype cleaning, as well as with general study coordination, was provided
by Health ABC Study (HABC) Investigators. The KORA dataset was obtained from the NEI
Refractive Error Collaboration (NEIREC) Database, support for which was provided by the
National Eye Institute. Support for genotyping of the COGEND samples, which was performed
at the Center for Inherited Disease Research (CIDR), was provided by 1X01 HG005274-01.
Assistance with genotype cleaning of the COGEND samples, as well as with general study
coordination, was provided by the Gene Environment Association Studies (GENEVA)
Coordinating Center (U01HG004446). Support for the collection of COGEND datasets and
samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND;
P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research
Center (P50 DA019706, P50 CA084724).
Lowther et al.
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Lowther C, Costain G, Stavropoulos DJ, et al. Delineating the 15q13.3 microdeletion
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2.
Dolcetti A, Silversides CK, Marshall CR, et al. 1q21.1 Microduplication expression in
adults. Genet Med 2013;15:282-289.
3.
Bushby KM, Cole T, Matthews JN, Goodship JA. Centiles for adult head circumference.
Arch Dis Child 1992;67(10):1286-1287.
4.
Rollins JD, Collins JS, Holden KR. United States head circumference growth reference
charts: birth to 21 years. J Pediatr 2010;156(6):907-913, 913 e901-902.
5.
Health Canada. Canadian Perinatal Health Report, 2008. Ottawa: Minister of Public
Works and Government Services Canada, 2008.
6.
Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian
reference for birth weight for gestational age. Pediatrics 2001;108(2):E35.