Nature Research€¦ · Web viewSupplementary material. Table of contents. Samples. CNV calling....

Supplementary material

Table of contents

I. Samples

II. CNV calling

III. List of CNVs and genes implicated in SCZ and other neurodevelopmental disorders

IV. Workflow of this study

V. Properties of identified CNVs

VI. Power analysis

VII. CNV validation

1) aCGH

2) Quantitative real-time PCR

3) Breakpoint sequencing

4) Gene expression analysis

VIII. Genome-wide CNV burden analysis

IX. Clinically significant CNVs

X. Evaluation of clinical characteristics

XI. Gene set analysis and SCZ candidate genes

XII. Identification of causal genes in SCZ-associated CNVs

XIII. Evaluation of inter-connectivity of SCZ candidate genes

XIV. Analyses excluding Taiwanese cases

1) Genome-wide CNV burden analysis

2) Clinically significant CNVs

3) Gene set analysis

4) SCZ candidate genes

5) Evaluation of inter-connectivity of SCZ candidate genes

I. Samples

Table S1. Characteristics of subjects in this study

Cases

Controls

P

n = 1745

n = 837

Male (%)

969 (55.5)

470 (56.1)

0.77

Mean age ± SD (years)

45.5 ± 15.8

39.3 ± 15.8

<0.001

Institutions where DNA was collected (ethnicity)

Nagoya University (Japanese)

893

738

Tokyo Metropolitan Institute of Medical Science (Japanese)

209

17

Toyama University (Japanese)

74

82

Tokushima University (Japanese)

16

-

Osaka University (Japanese)

128

-

Niigata University (Japanese)

111

-

Fujita Health University (Japanese)

62

-

RIKEN BSI Institute (Japanese)

36

-

Yuli Mental Health Research Center (Taiwanese)

216

-

　

Statistical differences were tested with the two-sided Fisher's exact test and Student's t-test for sex and age, respectively.

II. CNV calling

Table S2. Log2 ratio thresholds for loss and gain

Log2 ratio thresholds

CNV size

Loss

Gain

10-100 kb

−0.7

0.45

100-500 kb

−0.6

0.4

>500 kb

−0.4

0.3

The log2 ratio thresholds in this study are much more stringent than default thresholds of −0.2 (loss) and 0.17 (gain).

III. List of CNVs and genes implicated in SCZ and other neurodevelopmental disorders

Table S3. List of CNVs implicated in SCZ or other neurodevelopmental disorders

CNV Syndrome (genes)

Cytoband

CNV regions

Recurrent CNVs

1p36 deletion syndrome (GABRD)

1p36

chr1:0-10000000

1q21.1 deletion/duplication (TAR syndrome region, HFE2)

1q21.1

chr1:144000000-144340000

+

1q21.1 deletion/duplication syndrome (GJA5)

1q21.1

chr1:145040000-145860000

+

2q11.2 deletion (LMAN2L, ARID5A)

2q11.2

chr2:96090000-97040000

+

2q37 deletion syndrome (HDAC4)

2q37.3

chr2:239370000-242120000

　

3q29 deletion/duplication syndrome (DLG1)

3q29

chr3:197230000-198840000

+

Wolf-Hirschhorn syndrome (deletion, WHSC1, WHSC2)

4p16.3

chr4:1840000-1980000

　

Sotos syndrome (deletion, NSD1)

5q35.2-q35.3

chr5:175650000-176990000

+

Williams syndrome (deletion), 7q11.23 duplication syndrome (ELN, GTF2I)

7q11.23

chr7:72380000-73780000

+

8p23.1 deletion/duplication syndrome (SOX7, CLDN23)

8p23.1

chr8:8130000-11930000

+

9q34 deletion syndrome (EHMT1)

9q34.3

chr9:136950000-140200000

　

10q11.21-q11.23 deletion/duplication (CHAT, SLC18A3)

10q11.21-q11.23

chr10:48640000-51410000

+

10q23 deletion syndrome (NRG3, GRID1)

10q23.1-q23.2

chr10:81950000-88790000

+

Potocki-Shaffer syndrome (deletion, EXT2)

11p11.2

chr11:43940000-46020000

　

12q14 deletion syndrome (GRIP1, HMGA2)

12q14.3

chr12:63360000-66930000

　

13q12.12 deletion (SACS)

13q12.12

chr13:22440000-23790000

+

15q11.2 deletion syndrome (NIPA1)

15q11.2

chr15:20350000-20640000

+

Prader-Willi/Angelman syndrome, 15q11.2-q13.1 duplication syndrome

15q11.2-q13.1

chr15:21140000-26100000

+

15q13.1q13.2 deletion/duplication syndrome (APBA2)

15q13.1-q13.2

chr15:26860000-28160000

+

15q13.3 deletion/duplication syndrome (CHRNA7)

15q13.3

chr15:28700000-30270000

+

15q13.3 smaller deletion/duplication syndrome (CHRNA7)

15q13.3

chr15:29800000-30230000

+

15q24 deletion/duplication syndrome (FBXO22, TSPAN3)

15q24.1-q24.3

chr15:72170000-75960000

+

15q25.2 deletion syndrome (HOMER2, BNC1)

15q25.2

chr15:80980000-82530000

+

15q26 overgrowth syndrome

15q26.3

chr15:97180000-100340000

　

Rubinstein-Taybi syndrome (deletion)

16p13.3

chr16:3720000-3800000

+

16p13.11 deletion/duplication syndrome (MYH11)

16p13.11

chr16:15410000-16200000

+

16p11.2p12.1 deletion/duplication syndrome

16p11.2-p12.1

chr16:21260000-29350000

+

16p12.1 deletion/duplication syndrome (EEF2K, CDR2)

16p12.1

chr16:21850000-22370000

+

16p11.2 distal deletion/duplication syndrome (SH2B1)

16p11.2

chr16:28680000-29020000

+

16p11.2 deletion/duplication syndrome (TBX6)

16p11.2

chr16:29560000-30110000

+

17p13.3 deletion/duplication syndrome (YWHAE, PAFAH1B1)

17p13.3

chr17:50000-2540000

　

HNPP (PMP22)

17p12

chr17:14010000-15440000

+

Smith-Magenis syndrome (deletion)/Potocki-Lupski syndrome (duplication)

17p11.2

chr17:16650000-20420000

+

NF1 deletion/duplication syndrome

17q11.2

chr17:26190000-27240000

+

RCAD (renal cysts and diabetes) syndrome/17q12 duplication syndrome (HNF1B)

17q12

chr17:31890000-33280000

+

17q21.31 deletion/duplication syndrome (MAPT)

17q21.31

chr17:41060000-41540000

+

22q11.21 VCFS region deletion/duplication (3 Mb, COMT, CRKL)

22q11.21

chr22:17020000-20070000

+

22q11.21 VCFS region deletion/duplication (1.7 Mb, proximal, COMT)

22q11.21

chr22:17020000-18720000

+

22q11.21 VCFS region deletion/duplication (0.8 Mb, distal, CRKL)

22q11.21

chr22:19040000-19810000

+

22q11.22 (TOP3B) deletion

22q11.22

chr22:20640000-20900000

+

22q11.22-q11.23 deletion/duplication syndrome (ADORA2A, BCR)

22q11.22-q11.23

chr22:21300000-23370000

+

22q11.23 deletion/duplication syndrome (ADORA2A)

22q11.23

chr22:21990000-23370000

+　

Phelan-McDermid syndrome (deletion)/22q13 duplication (SHANK3)

22q13.33

chr22:49460000-49520000

　

Xp22.31 X-linked ichthyosis region (STS) deletion/duplication syndrome

Xp22.31

chrX:6400000-8100000

+

Turner syndrome (XO)

whole chrX

chrX:1-154910000

　

Klinefelter syndrome (XXY)

whole chrX

chrX:1-154910000

　

Triple X syndrome (XXX)

whole chrX

chrX:1-154910000

　

XYY syndrome

whole chrY

chrY:1-57770000

　

Recurrent CNVs are mediated by non-allelic homologous recombination.

Abbreviations: RCAD, renal cysts and diabetes syndrome; VCFS, velo-cardio-facial syndrome

Table S4. List of genes implicated in SCZ or other neurodevelopmental disorders

Gene symbol

Gene name

Cytoband

Gene scores in SFARI

ABCA13

ATP-binding cassette, sub-family A (ABC1), member 13

7p12.3

　

ADA

adenosine deaminase

20q13.12

3

ADNP

activity-dependent neuroprotector homeobox

20q13.13

1S

ADSL

adenylosuccinate lyase

22q13.1

S

AHI1

Abelson helper integration site 1

6q23.2

S

ALDH5A1

aldehyde dehydrogenase 5 family, member A1

6p22

S

ANK2

ankyrin 2, neuronal

4q25-q26

3

ANXA1

annexin A1

9q21.13

3

ARID1B

AT rich interactive domain 1B (SWI1-like)

6q25.3

3S

ARX

aristaless related homeobox

Xp21.3

S

ASTN2

astrotactin 2

9q33

3

ATP10A

ATPase, class V, type 10A

15q12

3

ATP2B2

ATPase, Ca++ transporting, plasma membrane 2

3p25.3

3

AUTS2

autism susceptibility candidate 2

7q11.22

3

AVPR1A

arginine vasopressin receptor 1A

12q14-q15

3

BCKDK

branched chain ketoacid dehydrogenase kinase

16p11.2

3

CACNA1C

calcium channel, voltage-dependent, L type, alpha 1C subunit

12p13.3

S

CACNA1H

calcium channel, voltage-dependent, T type, alpha 1H subunit

16p13.3

2

CACNB2

calcium channel, voltage-dependent, beta 2 subunit

10p12

3

CC2D1A

coiled-coil and C2 domain containing 1A

19p13.12

3

CDKL5

cyclin-dependent kinase-like 5

Xp22

S

CEP41

centrosomal protein 41 kDa

7q32

3

CHD2

chromodomain helicase DNA binding protein 2

15q26

3S

CHD7


8q12.2

S

CHD8


14q11.2

1

CHRM3

cholinergic receptor, muscarinic 3

1q43

　

CHRNA7

cholinergic receptor, nicotinic, alpha 7 (neuronal)

15q13.3

3

CNTN4

contactin 4

3p26.3

2

CNTNAP2

contactin associated protein-like 2

7q35

2S

CNTNAP4

contactin associated protein-like 4

16q23.1

3

CSMD1

CUB and Sushi multiple domains 1

8p23.2

　

CTNNB1

catenin (cadherin-associated protein), beta 1, 88 kDa

3p21

3

CUL3

cullin 3

2q36.2

3

DEAF1

DEAF1 transcription factor

11p15.5

2S

DHCR7

7-dehydrocholesterol reductase

11q13.4

S

DISC1

disrupted in schizophrenia 1

1q42.1

3

DLG2

discs, large homolog 2 (Drosophila)

11q21

　

DMD

dystrophin

Xp21.2

S

DMPK

dystrophia myotonica-protein kinase

19q13.3

S

DPYD

dihydropyrimidine dehydrogenase

1p22

　

DYRK1A

dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A

21q22.13

2

EHMT1

euchromatic histone-lysine N-methyltransferase 1

9q34.3

3S

FMR1

fragile X mental retardation 1

Xq27.3

S

FOXP1

forkhead box P1

3p14.1

3

FOXP2

forkhead box P2

7q31

3

GRID2

glutamate receptor, ionotropic, delta 2

4q22

　

GRIK2

glutamate receptor, ionotropic, kainate 2

6q16.3

3

GRIN2B

glutamate receptor, ionotropic, N-methyl-d-aspartate 2B

12p13.1

2

GRIP1

glutamate receptor interacting protein 1

12q13.13

2

HDAC4

histone deacetylase 4

2q37.3

S

HEPACAM

hepatic and glial cell adhesion molecule

11q24.2

S

HMGN1

high mobility group nucleosome binding domain 1

21q22.3

3

HOXA1

homeobox A1

7p15.2

S

ITGB3

integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)

17q21.32

3

KATNAL2

katanin p60 subunit A-like 2

18q21.1

3

KCNJ10

potassium channel, inwardly rectifying subfamily J, member 10

1q23.2

S

LAMB1

laminin, beta 1

7q22

3

LMX1B

LIM homeobox transcription factor 1, beta

9q33.3

3

MBD5

methyl-CpG binding domain protein 5

2q23.2

3S

MECP2

methyl CpG binding protein 2

Xq28

S

MET

MET proto-oncogene, receptor tyrosine kinase

7q31

2

NF1

neurofibromin 1

17q11.2

S

NIPBL

Nipped-B homolog (Drosophila)

5p13.2

S

NLGN3

neuroligin 3

Xq13.1

3

NLGN4X

neuroligin 4, X-linked

Xp22.33

3

NPAS3

neuronal PAS domain protein 3

14q13.1

　

NRXN1

neurexin 1

2p16.3

2

NRXN3

neurexin 3

14q31

3

NSD1

nuclear receptor binding SET domain protein 1

5q35

S

NTNG1

netrin G1

1p13.2-p13.1

4S

OPHN1

oligophrenin 1

Xq12

3

OXTR

oxytocin receptor

3p25

3

PARK2

parkin RBR E3 ubiquitin protein ligase

6q25.2-q27

　

PCDH19

protocadherin 19

Xq22.1

S

POGZ

pogo transposable element with ZNF domain

1q21.1

3

PON1

paraoxonase 1

7q21.3

3

PRKCB

protein kinase C, beta

16p12

3

PTCHD1

patched domain containing 1

Xp22.13

2

PTEN

phosphatase and tensin homolog

10q23

2S

PTPRM

protein tyrosine phosphatase, receptor type, M

18p11.2

　

RAI1

retinoic acid induced 1

17p11.2

S

RBFOX1

RNA binding protein, fox-1 homolog (C. elegans) 1

16p13.3

3

RELN

reelin

7q22

3

SCN1A

sodium channel, voltage gated, type I alpha subunit

2q24.3

S

SCN2A

sodium channel, voltage gated, type II alpha subunit

2q24.3

2

SEMA5A

sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5A

5p15.2

3

SETD5

SET domain containing 5

3p25.3

3S

SHANK1

SH3 and multiple ankyrin repeat domains 1

19q13.3

3

SHANK2


11q13.2

2

SHANK3


22q13.3

1S

SLC38A10

solute carrier family 38, member 10

17q25.3

3

SLC9A6

solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6

Xq26.3

S

SYNE1

spectrin repeat containing, nuclear envelope 1

6q25.2

4S

SYNGAP1

synaptic Ras GTPase activating protein 1

6p21.3

2S

TBR1

T-box, brain, 1

2q24.2

2

TMLHE

trimethyllysine hydroxylase, epsilon

Xq28

3

TSC1

tuberous sclerosis 1

9q34

S

TSC2

tuberous sclerosis 2

16p13.3

S

UBE3A

ubiquitin protein ligase E3A

15q11.2

S

ULK4

unc-51 like kinase 4

3p22.1

　

UPF3B

UPF3 regulator of nonsense transcripts homolog B (yeast)

Xq24

S

VIPR2

vasoactive intestinal peptide receptor 2

7q36.3

　

VPS13B

vacuolar protein sorting 13 homolog B (yeast)

8q22-q23

S

ZBTB20

zinc finger and BTB domain containing 20

3q13.2

3S

ZNF804A

zinc finger protein 804A

2q32.1

　

Gene scores in SFARI were obtained from https://gene.sfari.org/autdb/GS_Home.do. They include category S (syndromic), category 1 (high confidence), category 2 (strong candidate), category 3 (suggestive evidence), and category 4 (minimal evidence).

IV. Workflow of this study

Figure S1. CNV discovery, quality control (QC), and analysis

V. Properties of identified CNVs

Table S5. Comparison of the number and size of identified CNVs

Study

Present study (2015)

Szatkiewicz et al. (2014)1

Ikeda et al. (2010)2

Study design

case-control

case-control

case-control

platform

NimbleGen aCGH 720k

Affymetrix 5.0, Affymetrix 6.0, Illumina OmniExpress

Affymetrix 5.0 Arrays

CNVs analyzed

size

>10 kb

>100 kb

>100 kb

frequency

<1%

<1%

<1%

sample size (cases and controls)

2523

10636

1032

Number of CNVs

7066

9723

1052

Mean number of CNVs per sample

2.80

0.91

1.02

Median CNV size (kb)

48

182

204

Figure S2. Properties of 7066 rare CNVs identified in this study (cases and controls combined)

(a) Size distribution. (b) Types of CNVs in terms of genes: exonic, intronic, or intergenic. (c) The number of genes overlapping with CNVs. In (b) and (c), gene annotation from GENCODE version 21 was used. In (c), the number of genes with an exon that overlapped with a CNV was counted. Thus, 2374 CNVs with no genes included 741 intronic CNVs and 1633 intergenic CNVs.

VI. Power analysis

Table S6. Power to detect associations with 11 established SCZ-associated CNVs

CNVs

Disease allele frequency (%)

Genotype relative risk

Power

Dominant model

Additive model

Multiplicative model

1q21.1 deletion

0.011

8.35

0.27

0.27

0.27

1q21.1 duplication

0.019

3.45

0.15

0.15

0.15

NRXN1 deletion

0.01

9.01

0.28

0.28

0.28

3q29 deletion

0.0007

57.65

0.08

0.08

-

7q11.23 duplication

0.0029

11.35

0.12

0.12

0.12

15q11.2 deletion

0.14

2.15

0.25

0.25

0.25

15q11.2-q13.1 duplication

0.0032

13.2

0.14

0.14

-

15q13.3 deletion

0.0095

7.52

0.22

0.22

0.22

16p13.11 duplication

0.065

2.3

0.18

0.18

0.18

16p11.2 duplication

0.015

11.52

0.55

0.55

0.55

22q11.2 deletion

0.01

28.27

0.91

0.91

-

The power of this study (1699 cases and 824 controls) to detect significant associations with the 11 SCZ-associated CNVs is shown. Genotype relative risk and disease allele frequency in controls were obtained from the literature. The allele frequency for 22q11.2 deletion was set to 0.01% because it was not found in controls. “-” indicates that power could not be calculated.

VII. CNV validation

1) aCGH

Table S7. Summary of the validation rate for rare CNVs (aCGH)

CNV size

Deletion

Duplication

Average validation rate

Number of tested deletions

Number of validated deletions

Number of tested duplications

Number of validated duplications

10-20 kb

43

43

16

16

100.0%

20-30 kb

18

18

24

24

100.0%

30-40 kb

17

17

15

15

100.0%

40-50 kb

19

19

13

13

100.0%

50-60 kb

5

5

8

8

100.0%

60-70 kb

6

6

9

9

100.0%

70-80 kb

18

18

4

4

100.0%

80-90 kb

6

6

9

9

100.0%

90-100 kb

2

2

9

9

100.0%

100-200 kb

51

51

41

40

98.9%

200-300 kb

14

14

28

28

100.0%

300-400 kb

16

16

24

24

100.0%

400-500 kb

5

5

13

13

100.0%

500-600 kb

7

7

11

11

100.0%

600-700 kb

1

1

7

7

100.0%

700-800 kb

7

7

4

4

100.0%

800-900 kb

0

0

1

1

100.0%

900-1000 kb

1

1

5

5

100.0%

>1 Mb

36

36

24

24

100.0%

Total

272

272

265

264

99.8%

2) Quantitative real-time PCR (TaqMan copy number assays)

Table S8. Summary of the validation rate for rare CNVs (TaqMan copy number assays)

CNV size

Deletion

Duplication

Average validation rate

Number of tested deletions

Number of validated deletions

Number of tested duplications

Number of validated duplications

10-20 kb

103

103

81

79

98.9%

20-30 kb

2

2

1

1

100.0%

30-40 kb

2

2

0

0

100.0%

40-50 kb

2

2

0

0

100.0%

50-60 kb

0

0

0

0

-

60-70 kb

2

2

0

0

100.0%

70-80 kb

5

5

0

0

100.0%

80-90 kb

0

0

7

7

100.0%

90-100 kb

1

1

0

0

100.0%

100-200 kb

11

11

0

0

100.0%

200-300 kb

4

4

3

3

100.0%

300-400 kb

3

3

3

3

100.0%

400-500 kb

0

0

2

2

100.0%

500-600 kb

1

1

4

4

100.0%

600-700 kb

0

0

3

3

100.0%

700-800 kb

0

0

0

0

-

800-900 kb

0

0

0

0

-

900-1000 kb

0

0

0

0

-

>1 Mb

20

20

54

54

100.0%

Total

156

156

158

156

99.4%

3) Breakpoint sequencing

Table S9. Breakpoint sequencing for CNV validation

Deletion

Sample ID

CNV regions

Length (bp)

Inserted bases

Microhomology flanking insertions

Microhomology

Gene(s)

Possible mechanism(s)

SCZ0107

chr9:118484752-118677558

192806

ASTN2, TRIM32

NHEJ

SCZ1385

chr15:53294030-53307330

13300

CT

RAB27A

NHEJ, MMEJ, MMBIR

SCZ0844

chr9:118436464-118544113

107649

G

ASTN2, TRIM32

NHEJ

SCZ0218

chr6:17975205-17990576

15371

AAAATCATTTTAA

T

KIF13A

NHEJ, MMEJ, MMBIR

SCZ1215, SCZ0534, SCZ0315

chr16:81753280-81766209

12929

G

TACA

CDH13

NHEJ, MMEJ, MMBIR

SCZ0305

chr3:85586884-85646623

59739

GCT

CADM2

NHEJ, MMEJ, MMBIR

SCZ0499

chr7:8116886-8184053

67167

ACCGATAT

　

　

ICA1

NHEJ

SCZ0186

chrX:154414184-154438361

24177

　

　

　

TMLHE

NHEJ

SCZ0517

chr11:84264293-84352041

87748

TCTCACAATTCCT

　

　

DLG2

NHEJ

SCZ0969

chr15:81313575-81349140

35565

CCAGGC

HOMER2

NHEJ, MMEJ, MMBIR

SCZ0926

chr2:148464352-148823932

359580

　

MBD5

NHEJ

SCZ1175

chr4:149092791-149180089

87298

GCTTGTAACTTTCTTTGTATTTTTAGTAAAGACGA

ARHGAP10

MMBIR

SCZ0503

chr10:68001085-68090231

89146

GTGCTAGAGTTGTGCTAGAGAGTTGTGCTAG

TT

CTNNA3

NHEJ, MMEJ, MMBIR

SCZ0543

chr6:162275903-162400707

124804

TAAATG

PARK2

NHEJ

SCZ0952

chr6:162305772-162633940

328168

G

PARK2

NHEJ

SCZ1001

chr6:162536289-162665435

129146

GATA

PARK2

NHEJ, MMEJ, MMBIR

SCZ1518

chr8:3247384-3361508

114124

GC

CSMD1

NHEJ, MMEJ, MMBIR

SCZ0911

chr6:162507179-162629117

121938

AC

PARK2

NHEJ, MMEJ, MMBIR

SCZ0613

chr16:6622373-7016170

393797

AAAC

RBFOX1

NHEJ, MMEJ, MMBIR

SCZ1258

chr9:118490695-118535659

44964

GA

ASTN2, TRIM32

NHEJ, MMEJ, MMBIR

Duplication

Sample ID

CNV regions

Length

Duplication type

Bases inserted

Overlap

Gene

SCZ1521

chr7:116143695-116232037

88342

Tandem duplication

MET

SCZ0938

chr15:38933991-38978410

44419

Tandem duplication

GCC

VPS18

SCZ1088

chr11:129273655-129317227

43572

Tandem duplication

CCAGGCTGGTCTTGAACTCC

PRDM10

SCZ0949, SCZ1153

chr17:1181363-1209829

28466

Tandem duplication

YWHAE

SCZ0701

chrX:33040148-33067157

27009

Tandem duplication

DMD

SCZ0794

chr12:642485-668510

26025

Tandem duplication

NINJ2

SCZ1067

chr2:2117900-2263830

145930

Tandem duplication

GTGATATGGTTTGGCTGTGTCCCCACCCAAATCTCATCTTGAATTGTAGTTC

MYT1L

The position of the left break always defines the first base before the mutated sequence, and the position of the right break defines the last base within the mutated sequence. In the presence of microhomology, the breakpoints were placed to the right of the microhomology. When determining the location of breakpoints and inferring possible mechanisms, we referred to the previous literature.3 The coordinates are based on the UCSC human genome assembly hg18. Of the 20 sequenced deletion breakpoints, nine (45%) showed 1-35 bp of inserted sequence at the breakpoints, and 11 (55%) showed 1-6 bases of microhomologies. Three (15%) showed both sequence insertion and microhomologies at the breakpoints. MMBIR is a DNA replication-based mechanism for repair of single-sided double-strand breaks (DSBs). NHEJ is a recombination-based mechanism for repair of DNA DSBs.

Abbreviations: NHEJ, nonhomologous end joining; MMEJ, microhomology-mediated end joining; MMBIR, microhomology-mediated break-induced replication

4) Gene expression analysis

Method: Lymphoblastoid cell lines derived from subjects with and without target CNVs (Table S10) were established with the widely used Epstein-Barr virus transformation method with minor modification.4 Total RNA was extracted from lymphoblastoid cell lines using the RNAqueous Kit (Ambion, Austin, TX, USA), treated with DNase to remove contaminating genomic DNA using the TURBO DNA-free Kit (Ambion), and then reverse transcribed to cDNA with a high-capacity RNA-to-cDNA Kit (Applied Biosystems, Foster City, CA, USA). Two housekeeping genes, beta-2-microglobulin (B2M) and glucuronidase-beta (GUSB), were selected as internal control genes to normalize the polymerase chain reaction (PCR). Quantitative real-time PCR was performed on a ABI Prism 7900HT Real-Time PCR System (Applied Biosystems) using predesigned TaqMan Gene Expression Assay probes (Hs00289233_m1 for MBD5, Hs00383168_m1 for FBXO45, Hs01121472_m1 for SEPT14, Hs00382694_m1 for PCLO, Hs00215450_m1 for VPS13B, Hs00265843_m1 for DLG2, Hs00930485_m1 for CACNA1C, Hs01394304_m1 for SYT10, Hs00383168_m1 for CYFIP1, Hs00165556_m1 for PMP22, Hs01124540_m1 for PTPRM, Hs00996676_m1 for STS, Hs00214399_m1 for NDE1, Hs00374462_m1 for ARHGEF6, Hs99999907_m1 for B2M, and Hs99999908_ml for GUSB; Applied Biosystems). The cycle threshold was measured in duplicate. The data, including amplifying efficiency and relative expression with quantification, were analyzed using the comparative cycle threshold method.5

Statistical tests: Expression levels in subjects with target CNVs were compared with those in the schizophrenia group without target CNVs or the control group without target CNVs, and statistical significance was determined with a two-sided Z test. The significance level was set at 0.05.

Table S10. Target genes (CNVs) for expression analysis

Target gene

Event type

CNV region

CNV Size (bp)

Disease

Sample ID

MBD5

Del

chr2:148468658-148822197

353 539

SCZ

SCZ0926

FBXO45

Del

chr3:197222416-198817395

1 594 979

SCZ

SCZ0801

SEPT14

Del

chr7:55878360-55975143

96 783

SCZ

SCZ1203

PCLO

Del

chr7:80952886-83562074

2 609 188

SCZ

SCZ1331

VPS13B

Del

chr8:100139034-100307029

167 995

SCZ

SCZ0714

DLG2

Del

chr11:83504379-84034653

530 274

SCZ

SCZ1290

CACNA1C

Del

chr12:2669110-2711779

42 669

SCZ

SCZ0607

SYT10

Del

chr12:33349158-33513957

164 799

SCZ

SCZ0708

SYT10

Del

chr12:33349158-33513957

164 799

SCZ

SCZ0715

CYFIP1

Del

chr15:19818769-20845066

1 026 297

CONT

CON0343

CYFIP1

Del

chr15:20311079-20672108

361 029

SCZ

SCZ0721

PMP22

Del

chr17:14024195-15360833

1 336 638

SCZ

SCZ1274

PTPRM

Del

chr18:7766839-8237508

470 669

SCZ

SCZ1051

STS

Del

chrX:6708608-7850492

1 141 884

SCZ

SCZ0843

NDE1

Dup

chr16:15033258-16514211

1 480 953

SCZ

SCZ0714

STS

Dup

chrX:6466758-8079237

1 612 479

SCZ

SCZ0716

STS

Dup

chrX:6696983-7724618

1 027 635

SCZ

SCZ1200

ARHGEF6

Dup

chrX:135449062-135793171

344 109

SCZ

SCZ1343

Abbreviations: CONT, control; Del, deletion; Dup, duplication; SCZ, schizophrenia

Results

Figure S3. Gene expression results of CNVs

(a)

(b)

Sample ID

CNV

Vs. SCZ group

Vs. CONT group

Z score

P

Z score

P

SCZ0926

MBD5 Del

−3.1

0.0020

−2.0

0.043

SCZ0801

FBXO45 Del

−2.3

0.021

−2.8

0.0049

SCZ1203

SEPT14 Del

−1.1

0.27

−0.9

0.38

SCZ1331

PCLO Del

−0.8

0.41

−1.3

0.19

SCZ0714

VPS13B Del

−3.4

0.00080

−2.2

0.031

SCZ1290

DLG2 Del

−1.5

0.14

−1.7

0.09

SCZ0607

CACNA1C Del

−1.9

0.06

−1.4

0.15

SCZ0708

SYT10 Del

−3.3

0.0011

−3.6

0.00032

SCZ0715

SYT10 Del

−3.3

0.0011

−3.6

0.00032

CON0343

CYFIP1 Del

−2.4

0.017

−2.9

0.0035

SCZ0721

CYFIP1 Del

−2.2

0.027

−2.7

0.0070

SCZ1274

PMP22 Del

−0.8

0.43

−0.8

0.43

SCZ1051

PTPRM Del

−1.0

0.31

−1.0

0.30

SCZ0843

STS Del

−2.8

0.0052

−2.5

0.013

SCZ0714

NDE1 Dup

1.7

0.09

4.8

0.0000017

SCZ0716

STS Dup

3.6

0.00031

3.5

0.00050

SCZ1200

STS Dup

5.3

0.00000013

5.0

0.00000045

SCZ1343

ARHGEF6 Dup

3.4

0.00062

4.3

0.000015

(a) Each dot [diamond: sample with deletion (Del), circle: sample with duplication (Dup), square: schizophrenia　(SCZ), and triangle: controls (CONT)] represents the relative expression value of each sample calculated by the 2−ΔΔCT method. The gray and white dots represent outlier and undetermined values, respectively. (b) Results for statistical tests. Abbreviations: CONT, control; Del, deletion; Dup, duplication; SCZ, schizophrenia

VIII. Genome-wide CNV burden analysis

Table S11. Genome-wide CNV burden analysis: CNV number

Event type

Frequency/size

CNV (n)

Mean number of cases

Mean number of controls

Case/Control ratio

OR (95% CI)

Pemp

Del & Dup

All

4692

1.91

1.75

1.09

1.08 (1.02, 1.15)

0.0041

Del & Dup

1×

1133

0.46

0.43

1.06

1.06 (0.93, 1.19)

0.2

Del & Dup

2-6×

2128

0.87

0.79

1.1

1.09 (1, 1.19)

0.029

Del & Dup

7×+

1779

0.73

0.65

1.12

1.11 (1.01, 1.22)

0.016

Del & Dup

10-100 kb

2722

1.09

1.06

1.02

1.02 (0.94, 1.1)

0.31

Del & Dup

100-200 kb

805

0.32

0.31

1.03

1.03 (0.89, 1.19)

0.33

Del & Dup

200-500 kb

729

0.3

0.26

1.15

1.14 (0.98, 1.33)

0.042

Del & Dup

500 kb+

436

0.2

0.11

1.79

1.55 (1.25, 1.93)

0.00004

Del

All

2037

0.82

0.77

1.06

1.06 (0.97, 1.17)

0.099

Del

1×

604

0.25

0.22

1.13

1.13 (0.95, 1.34)

0.085

Del

2-6×

832

0.34

0.31

1.1

1.1 (0.95, 1.27)

0.11

Del

7×+

763

0.3

0.3

1.01

1.01 (0.87, 1.17)

0.43

Del

10-100 kb

1379

0.54

0.56

0.97

0.97 (0.87, 1.09)

0.69

Del

100-200 kb

305

0.13

0.1

1.26

1.25 (0.97, 1.6)

0.04

Del

200-500 kb

231

0.1

0.08

1.19

1.19 (0.89, 1.58)

0.12

Del

500 kb+

122

0.06

0.03

1.71

1.6 (1.07, 2.4)

0.0081

Dup

All

2655

1.09

0.98

1.12

1.1 (1.02, 1.18)

0.0085

Dup

1×

809

0.33

0.3

1.09

1.08 (0.94, 1.24)

0.14

Dup

2-6×

1159

0.47

0.43

1.09

1.08 (0.96, 1.22)

0.1

Dup

7×+

857

0.36

0.31

1.16

1.13 (0.99, 1.29)

0.037

Dup

10-100 kb

1343

0.55

0.51

1.08

1.08 (0.96, 1.21)

0.11

Dup

100-200 kb

500

0.19

0.21

0.92

0.93 (0.78, 1.11)

0.78

Dup

200-500 kb

498

0.21

0.18

1.14

1.13 (0.94, 1.35)

0.11

Dup

500 kb+

314

0.15

0.08

1.82

1.55 (1.2, 2)

0.00012

Abbreviations: Del, deletion; Dup, duplication; OR, odds ratio; CI, confidence interval

Pemp, empirical P values were obtained by 100 000 permutations.

Table S12. Genome-wide CNV burden analysis: CNV length

Event type

Frequency/size

CNV (n)

Mean length of cases

(100 kb)

Mean length of controls

(100 kb)

Case/Control ratio

OR (95% CI)

Pemp

Del & Dup

All

4692

13.61

2.66

5.12

1.05 (1.03, 1.07)

0.00001

Del & Dup

1×

1133

0.62

0.57

1.09

1.02 (0.97, 1.08)

0.22

Del & Dup

2-6×

2128

2.29

1.5

1.53

1.04 (1.02, 1.07)

0.00004

Del & Dup

7×+

1779

11.32

0.92

12.37

1.06 (1.02, 1.1)

0.00001

Del & Dup

10-100 kb

2722

0.46

0.46

1

1 (0.85, 1.17)

0.5

Del & Dup

100-200 kb

805

0.46

0.45

1.03

1.02 (0.92, 1.12)

0.36

Del & Dup

200-500 kb

729

0.97

0.84

1.16

1.04 (0.99, 1.09)

0.041

Del & Dup

500 kb+

436

11.71

0.91

12.87

1.05 (1.03, 1.08)

0.00001

Del

All

2037

1.42

0.88

1.61

1.06 (1.03, 1.1)

0.00009

Del

1×

604

0.31

0.23

1.35

1.09 (0.99, 1.19)

0.034

Del

2-6×

832

0.82

0.45

1.81

1.06 (1.01, 1.1)

0.0017

Del

7×+

763

0.61

0.34

1.79

1.06 (1.01, 1.12)

0.0047

Del

10-100 kb

1379

0.22

0.24

0.95

0.9 (0.72, 1.14)

0.81

Del

100-200 kb

305

0.19

0.15

1.28

1.18 (0.99, 1.4)

0.027

Del

200-500 kb

231

0.3

0.26

1.18

1.05 (0.96, 1.15)

0.13

Del

500 kb+

122

0.71

0.25

2.88

1.07 (1.02, 1.11)

0.00026

Dup

All

2655

12.19

1.78

6.86

1.04 (1.01, 1.06)

0.00001

Dup

1×

809

0.58

0.52

1.12

1.02 (0.97, 1.08)

0.19

Dup

2-6×

1159

1.37

0.96

1.43

1.03 (1, 1.06)

0.0071

Dup

7×+

857

10.49

0.49

21.31

1.04 (0.99, 1.09)

0.00048

Dup

10-100 kb

1343

0.24

0.23

1.06

1.1 (0.88, 1.38)

0.2

Dup

100-200 kb

500

0.27

0.3

0.91

0.94 (0.83, 1.06)

0.84

Dup

200-500 kb

498

0.67

0.58

1.15

1.04 (0.98, 1.1)

0.091

Dup

500 kb+

314

11

0.66

16.57

1.04 (1.01, 1.07)

0.00001

Abbreviations: Del, deletion; Dup, duplication; OR, odds ratio; CI, confidence interval

Pemp, empirical P values were obtained by 100 000 permutations.

Kushima et al

6

IX. Clinically significant CNVs

Table S13. Clinically significant CNVs identified in this study

Disease

Sample ID

Age/Sex

Cytoband

CNV region

CNV Size (bp)

Event Type

De novo/Inherited

Notes

Previous findings

SCZ

ID/DD

ASD

ADHD

Epilepsy

SCZ

SCZ1589

39/M

1p21.3

chr1:97992817-98115275

122 459

Del

　

DPYD

+

+

+

　

　

SCZ

SCZ0242

66/F

1q21.1

chr1:144100334-144643106

542 773

Del

　

Recurrent CNV

+

+

　

　

　

SCZ

SCZ1194

67/M

1q21.1

chr1:144100334-144605947

505 614

Del

　

Recurrent CNV

+

+

　

　

　

SCZ

SCZ0690

36/M

1q21.1

chr1:144108801-144722446

613 646

Dup

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0288

74/F

1q21.1

chr1:144461364-146362307

1 900 944

Del

　

Recurrent CNV (SCZ-associated CNV)

+

+

+

　

+

SCZ

SCZ0503

49/F

1q21.1

chr1:144461364-146362307

1 900 944

Del

　


+

+

+

　

+

SCZ

SCZ0952

47/F

1q21.1

chr1:144461364-146362307

1 900 944

Del

　


+

+

+

　

+

SCZ

SCZ0194

50/F

1q21.1

chr1:144473958-146362307

1 888 350

Del

　


+

+

+

　

+

CONT

CON0202

26/M

1q42.2

chr1:230212137-230231594

19 458

Del

　

DISC1

+

　

+

　

　

SCZ

SCZ0225

56/F

1q43

chr1:237768058-237791044

22 987

Del

　

CHRM3

　

+

+

　

　

SCZ

SCZ1271

38/F

2p25.1-p24.3

chr2:11243595-16158159

4 914 565

Del

　

Large nonrecurrent CNVs

　

+

　

　

　

SCZ

SCZ0902

69/F

2p16.3

chr2:50802972-51020497

217 526

Del

　

NRXN1

+

+

+

+

+

SCZ

SCZ1410

17/M

2p15

chr2:61454895-62574071

1 119 177

Dup

De novo


　

　

　

　

　

SCZ

SCZ1051

48/M

2q11.2

chr2:96102134-97105800

1 003 667

Del

　

Recurrent CNV

　

+

+

　

+

CONT

CON0787

25/F

2q12.2-q12.3

chr2:106232245-107887902

1 655 658

Dup

　

Recurrent CNV

　

　

　

　

　

SCZ

SCZ1181

59/F

2q12.2-q12.3

chr2:106270313-107795050

1 524 738

Dup

　

Recurrent CNV

　

　

　

　

　

SCZ

SCZ0208

47/F

2q12.2-q12.3

chr2:106463273-107808880

1 345 608

Del

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ1092

53/M

2q21.1

chr2:131205332-131633413

428 082

Del

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0926

51/M

2q23.1

chr2:148468659-148822197

353 539

Del

　

MBD5

　

+

+

　

+

SCZ

SCZ0439

35/F

2q23.1

chr2:148616715-148715761

99 047

Del

Inherited

MBD5

　

+

+

　

+

SCZ

SCZ0027

31/M

2q23.1

chr2:148633233-148694098

60 866

Del

Inherited

MBD5

　

+

+

　

+

SCZ

SCZ0097

25/M

2q23.1

chr2:148690256-148879455

189 200

Del

De novo

MBD5

　

+

+

　

+

CONT

CON0292

27/F

2q23.1

chr2:148706096-148779523

73 428

Del

　

MBD5

　

+

+

　

+

SCZ

SCZ0639

65/M

2q32.1

chr2:185409856-185451359

41 504

Del

　

ZNF804A

+

　

　

　

　

CONT

CON0200

26/M

3p26.3

chr3:2316687-2593684

276 998

Del

　

CNTN4

　

+

+

　

　

CONT

CON0362

32/F

3p26.3

chr3:2625786-2707795

82 010

Del

　

CNTN4

　

+

+

　

　

CONT

CON0426

59/F

3p26.3

chr3:2625786-2707795

82 010

Del

　

CNTN4

　

+

+

　

　

SCZ

SCZ0070

33/F

3p22.1

chr3:41631078-41817206

186 129

Del

　

ULK4

+

　

　

　

　

SCZ

SCZ0564

37/M

3p22.1

chr3:41786353-41873725

87 373

Del

　

ULK4

+

　

　

　

　

SCZ

SCZ1640

41/M

3q24

chr3:147961935-149128701

1 166 767

Del

　


　

+

　

　

+

SCZ

SCZ0094

30/F

3q29

chr3:197222417-198817395

1 594 979

Del

De novo


+

+

+

　

+

SCZ

SCZ0801

55/F

3q29

chr3:197222417-198817395

1 594 979

Del

De novo


+

+

+

　

+

SCZ

SCZ1537

52/F

4p14-p13

chr4:39053592-42081810

3 028 219

Dup

　


　

+

　

　

　

SCZ

SCZ1083

20/M

4q22.2

chr4:94073748-94231533

157 786

Del

Inherited

GRID2

　

+

+

　

+

SCZ

SCZ0827

61/F

6q25.2

chr6:152969177-154861420

1 892 244

Dup

　


　

　

　

　

　

CONT

CON0320

31/F

6q26

chr6:162128484-162329816

201 333

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0543

51/M

6q26

chr6:162279108-162398622

119 515

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0952

47/F

6q26

chr6:162310184-162632839

322 656

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0234

16/F

6q26

chr6:162487216-162566217

79 002

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0911

64/F

6q26

chr6:162507763-162627601

119 839

Del

　

PARK2

+

+

+

+

　

CONT

CON0211

31/M

6q26

chr6:162512083-162641767

129 685

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1001

34/F

6q26

chr6:162537232-162660383

123 152

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1583

48/F

6q26

chr6:162548951-162759067

210 117

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1679

65/M

6q26

chr6:162555236-162719366

164 131

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1598

50/M

6q26

chr6:162602473-162865273

262 801

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1361

31/F

6q26

chr6:162607391-162768964

161 574

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0199

43/M

6q26

chr6:162610095-162641767

31 673

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ1199

51/M

6q26

chr6:162632839-162898128

265 290

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0420

24/F

6q26

chr6:162651207-162967066

315 860

Del

Inherited

PARK2

+

+

+

+

　

SCZ

SCZ1360

29/M

6q26

chr6:162677323-162835583

158 261

Del

　

PARK2

+

+

+

+

　

CONT

CON0350

24/F

6q26

chr6:162725441-162808218

82 778

Del

　

PARK2

+

+

+

+

　

SCZ

SCZ0460

27/M

6q26

chr6:162952428-163152518

200 091

Del

Inherited

PARK2

+

+

+

+

　

SCZ

SCZ0088

24/F

7q11.23

chr7:72365915-73776177

1 410 263

Dup

　


+

+

+

　

　

SCZ

SCZ1331

51/F

7q21.11

chr7:80952887-83562074

2 609 188

Del

De novo


　

　

　

　

+

SCZ

SCZ0782

53/M

7q22.1

chr7:102919640-102930809

11 170

Del

Inherited

RELN

+

　

+

　

　

SCZ

SCZ0259

43/F

7q31.1

chr7:109938707-112209817

2 271 111

Dup

　


　

　

　

　

　

CONT

CON0148

62/M

7q35

chr7:146089110-146129636

40 527

Del

　

CNTNAP2

+

+

+

+

+

SCZ

SCZ1495

47/M

7q36.3

chr7:158451300-158681438

230 139

Dup

　

VIPR2

+

　

+

　

　

SCZ

SCZ1164

37/F

8p23.2

chr8:2573916-4761131

2 187 216

Del

　


+

+

+

　

　

SCZ

SCZ1518

63/M

8p23.2

chr8:3254762-3359114

104 353

Del

　

CSMD1

+

+

+

　

　

SCZ

SCZ0494

38/M

8p23.2

chr8:3718760-3801316

82 557

Del

　

CSMD1

+

+

+

　

　

SCZ

SCZ0369

57/F

8p23.2

chr8:3726713-3801316

74 604

Del

　

CSMD1

+

+

+

　

　

CONT

CON0643

29/M

8p23.2

chr8:3726713-3801316

74 604

Del

　

CSMD1

+

+

+

　

　

SCZ

SCZ0388

43/M

8p23.2

chr8:3726713-3801316

74 604

Del

　

CSMD1

+

+

+

　

　

SCZ

SCZ0714

40/F

8q22.2

chr8:100139035-100307029

167 995

Del

Inherited

VPS13B

　

+

+

　

+

SCZ

SCZ1685

53/F

9q22.33-q31.2

chr9:101379231-108589175

7 209 945

Del

　


　

　

　

　

　

SCZ

SCZ0844

69/F

9q33.1

chr9:118438378-118543911

105 534

Del

　

ASTN2, TRIM32

+

+

+

+

+

SCZ

SCZ0107

36/M

9q33.1

chr9:118492592-118675446

182 855

Del

ASTN2, TRIM32

+

+

+

+

+

SCZ

SCZ1258

64/M

9q33.1

chr9:118492592-118534887

42 296

Del

　

ASTN2, TRIM32

+

+

+

+

+

SCZ

SCZ0896

46/F

10p15.2-p15.1

chr10:3110676-6286817

3 176 142

Dup

　


　

　

　

　

　

SCZ

SCZ1658

49/F

10q11.22-q11.23

chr10:46383972-51402930

5 018 959

Dup

　

Recurrent CNV

+

+

+

+

+

SCZ

SCZ1290

58/F

11q14.1

chr11:83504380-84034653

530 274

Del

　

DLG2

+

　

　

　

　

SCZ

SCZ0277

54/F

11q14.1

chr11:84203592-84370927

167 336

Del

　

DLG2

+

　

　

　

　

SCZ

SCZ0517

37/M

11q14.1

chr11:84267756-84350092

82 337

Del

　

DLG2

+

　

　

　

　

SCZ

SCZ0616

60/M

11q23.3-q25

chr11:118369519-134444816

16 075 298

Dup

　


　

+

　

　

　

SCZ

SCZ0607

49/M

12p13.33

chr12:2669111-2711779

42 669

Del

　

CACNA1C

　

　

+

　

　

SCZ

SCZ1198

63/F

13q12.12

chr13:22442669-23791183

1 348 515

Del

　

Recurrent CNV

　

　

　

　

　

SCZ

SCZ0824

67/F

14q13.1

chr14:32861152-32916252

55 101

Del

　

NPAS3

+

+

　

　

　

SCZ

SCZ1526

59/F

14q31.1

chr14:78424104-78730293

306 190

Del

　

NRXN3

　

　

+

　

　

CONT

CON0343

37/M

15q11.2

chr15:19818770-20845066

1 026 297

Del

　


+

+

+

+

　

SCZ

SCZ0593

57/F

15q11.2

chr15:20214229-20737623

523 395

Del

　


+

+

+

+

　

SCZ

SCZ1661

42/F

15q11.2

chr15:20214229-20690583

476 355

Del

　


+

+

+

+

　

CONT

CON0345

27/F

15q11.2

chr15:20311080-20636781

325 702

Del

　


+

+

+

+

　

CONT

CON0525

20/F

15q11.2

chr15:20311080-20633569

322 490

Del

　


+

+

+

+

　

CONT

CON0710

60/F

15q11.2

chr15:20311080-20784459

473 380

Del

　


+

+

+

+

　

SCZ

SCZ0721

48/M

15q11.2

chr15:20311080-20672108

361 029

Del

　


+

+

+

+

　

SCZ

SCZ0824

67/F

15q11.2

chr15:20311080-20672108

361 029

Del

　


+

+

+

+

　

SCZ

SCZ0903

65/F

15q11.2

chr15:20311080-20636781

325 702

Del

　


+

+

+

+

　

SCZ

SCZ0931

63/M

15q11.2

chr15:20311080-20672108

361 029

Del

　


+

+

+

+

　

SCZ

SCZ1012

41/M

15q11.2

chr15:20311080-20747796

436 717

Del

　


+

+

+

+

　

SCZ

SCZ1054

54/M

15q11.2

chr15:20311080-20636781

325 702

Del

　


+

+

+

+

　

SCZ

SCZ1387

20/M

15q11.2

chr15:20311080-20636781

325 702

Del

Inherited


+

+

+

+

　

SCZ

SCZ1657

71/F

15q11.2

chr15:20311080-20737623

426 544

Del

　


+

+

+

+

　

SCZ

SCZ1259

40/F

15q11.2-q13.1

chr15:21144837-26726521

5 581 685

Dup

Inherited


+

+

+

　

+

SCZ

SCZ0083

25/F

15q13.1-q13.2

chr15:26866219-28542654

1 676 436

Del

Inherited

Recurrent CNV

+

　

　

　

　

SCZ

SCZ1563

49/F

15q13.1-q13.2

chr15:26866219-28153380

1 287 162

Dup

　

Recurrent CNV

+

　

　

　

　

SCZ

SCZ0144

18/F

15q13.1-q13.2

chr15:27007910-28466332

1 458 423

Dup

De novo

Recurrent CNV

+

　

　

　

　

SCZ

SCZ0980

68/F

15q13.1-q13.2

chr15:27007910-28452255

1 444 346

Dup

　

Recurrent CNV

+

　

　

　

　

SCZ

SCZ0856

69/M

15q13.2-q13.3

chr15:28670193-30226345

1 556 153

Dup

　

Recurrent CNV

　

+

+

+

　

CONT

CON0018

29/F

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

CONT

CON0704

27/M

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ0863

35/F

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1358

62/M

15q13.3

chr15:29811492-30335754

524 263

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1432

46/F

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1487

43/M

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1559

44/F

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1575

32/M

15q13.3

chr15:29811492-30226345

414 854

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ0732

71/M

15q13.3

chr15:29816893-30442573

625 681

Dup

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ0622

72/M

15q24.1-q24.3

chr15:72171336-75954661

3 783 326

Dup

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0886

46/M

15q26.3

chr15:98702902-100217471

1 514 570

Dup

　


　

+

　

　

　

SCZ

SCZ0474

50/M

16p13.3

chr16:1179946-1240071

60 126

Del

De novo

CACNA1H

　

　

+

　

+

SCZ

SCZ0613

64/F

16p13.2

chr16:6622444-7009816

387 373

Del

　

RBFOX1

　

+

+

　

+

CONT

CON0005

43/F

16p13.2

chr16:6630996-6803284

172 289

Del

　

RBFOX1

　

+

+

　

+

SCZ

SCZ0839

62/F

16p13.2

chr16:6654642-6732837

78 196

Del

　

RBFOX1

　

+

+

　

+

SCZ

SCZ0076

28/F

16p13.2

chr16:7028522-7087701

59 180

Del

Inherited

RBFOX1

　

+

+

　

+

SCZ

SCZ0714

40/F

16p13.11

chr16:15033259-16514211

1 480 953

Dup

Inherited


+

+

+

　

+

SCZ

SCZ0030

34/F

16p13.11-p12.3

chr16:15088102-18686367

3 598 266

Dup

　


+

+

+

　

+

SCZ

SCZ0673

22/F

16p13.11

chr16:15320011-16294070

974 060

Dup

　


+

+

+

　

+

SCZ

SCZ0240

39/M

16p13.11

chr16:15331871-16444792

1 112 922

Del

　

Recurrent CNV

　

+

+

　

+

CONT

CON0290

30/F

16p13.11

chr16:15400571-16411219

1 010 649

Del

　

Recurrent CNV

　

+

+

　

+

SCZ

SCZ0601

49/M

16p12.1

chr16:21857845-22343083

485 239

Del

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0921

50/F

16p12.1

chr16:21857845-22352966

495 122

Dup

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0035

31/M

16p11.2

chr16:28289694-29243098

953 405

Del

Inherited

Recurrent CNV

+

+

+

　

　

CONT

CON0451

54/F

16p11.2

chr16:29526156-30100063

573 908

Dup

　


+

+

+

+

+

SCZ

SCZ0818

47/F

16p11.2

chr16:29539540-30100063

560 524

Dup

　


+

+

+

+

+

SCZ

SCZ0819

57/M

16p11.2

chr16:29553777-30100063

546 287

Dup

　


+

+

+

+

+

SCZ

SCZ1010

56/F

16p11.2

chr16:29553777-30100063

546 287

Del

　

Recurrent CNV

　

+

+

+

+

SCZ

SCZ0110

18/M

16p11.2

chr16:29564890-30100063

535 174

Dup

De novo


+

+

+

+

+

CONT

CON0043

30/M

17p12

chr17:14017900-15433888

1 415 989

Del

　

Recurrent CNV

+

　

　

　

　

SCZ

SCZ1274

60/F

17p12

chr17:14024196-15360833

1 336 638

Del

　

Recurrent CNV

+

　

　

　

　

CONT

CON0274

22/F

17q12

chr17:31435685-33624959

2 189 275

Dup

　

Recurrent CNV

+

+

+

　

　

SCZ

SCZ1051

48/M

18p11.23

chr18:7766840-8237508

470 669

Del

　

PTPRM

+

　

　

　

　

CONT

CON0184

28/F

18p11.23

chr18:8006720-8021358

14 639

Del

　

PTPRM

+

　

　

　

　

SCZ

SCZ0265

21/F

18q21.1

chr18:42828743-42855335

26 593

Del

　

KATNAL2

　

　

+

　

　

SCZ

SCZ0763

59/F

19q13.2-q13.31

chr19:46811356-49506179

2 694 824

Dup

　


　

　

　

　

　

SCZ

SCZ0007

59/M

22q11.21

chr22:17024062-20056851

3 032 790

Del

　


+

+

+

+

+

SCZ

SCZ0459

20/F

22q11.21

chr22:17024062-20037371

3 013 310

Del

De novo


+

+

+

+

+

SCZ

SCZ0897

44/F

22q11.21

chr22:17024062-20037371

3 013 310

Del

　


+

+

+

+

+

SCZ

SCZ1231

36/F

22q11.21

chr22:17024062-20056851

3 032 790

Del

　


+

+

+

+

+

SCZ

SCZ1497

39/M

22q11.21

chr22:17024062-20056851

3 032 790

Del

　


+

+

+

+

+

SCZ

SCZ1645

52/M

22q11.21

chr22:17024062-20087703

3 063 642

Del

　


+

+

+

+

+

SCZ

SCZ1678

41/M

22q11.21

chr22:17025596-19365543

2 339 948

Del

　


+

+

+

+

+

SCZ

SCZ1130

30/M

22q11.21

chr22:17176197-20026630

2 850 434

Del

　


+

+

+

+

+

SCZ

SCZ1299

37/F

22q11.21

chr22:17201569-19790598

2 589 030

Del

　


+

+

+

+

+

SCZ

SCZ0686

40/F

22q11.21

chr22:17227336-19896035

2 668 700

Del

　


+

+

+

+

+

SCZ

SCZ0096

23/M

22q11.21

chr22:17269529-19790598

2 521 070

Del

De novo


+

+

+

+

+

SCZ

SCZ0320

33/F

22q11.21

chr22:17269529-19365543

2 096 015

Del

　


+

+

+

+

+

SCZ

SCZ1228

52/F

22q11.21

chr22:17269529-19790598

2 521 070

Del

　


+

+

+

+

+

SCZ

SCZ1488

41/F

22q11.21

chr22:17269529-18691906

1 422 378

Del

　


+

+

+

+

+

SCZ

SCZ1592

60/F

22q11.21

chr22:17269529-19790598

2 521 070

Del

　


+

+

+

+

+

SCZ

SCZ0858

57/M

22q11.21

chr22:18871966-19825156

953 191

Del

　

Recurrent CNV

　

+

　

　

　

SCZ

SCZ0497

18/F

22q11.21

chr22:19051034-19790598

739 565

Del

　

Recurrent CNV

　

+

　

　

　

CONT

CON0656

23/F

22q11.22

chr22:20650930-20896160

245 231

Del

　

Recurrent CNV

+

+

+

　

　

SCZ

SCZ1505

29/F

22q11.22

chr22:20650930-20896160

245 231

Del

　

Recurrent CNV

+

+

+

　

　

SCZ

SCZ1511

34/M

22q11.22

chr22:20650930-20896160

245 231

Del

　

Recurrent CNV

+

+

+

　

　

SCZ

SCZ1006

53/M

22q11.22-q11.23

chr22:21301580-23371986

2 070 407

Dup

　

Recurrent CNV

+

+

　

　

　

SCZ

SCZ0011

21/F

22q11.23

chr22:21997751-23321609

1 323 859

Dup

Inherited

Recurrent CNV

+

+

　

　

　

SCZ

SCZ0134

32/M

22q11.23

chr22:21997751-23371986

1 374 236

Dup

Inherited

Recurrent CNV

+

+

　

　

　

SCZ

SCZ0051

39/F

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXX

　

　

+

+

+

SCZ

SCZ0160

29/M

whole chrX

chrX:1-154913754

154 913 754

Dup

De novo

XXY

+

+

+

+

+

SCZ

SCZ0240

39/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY

+

+

+

+

+

SCZ

SCZ0270

60/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY

+

+

+

+

+

SCZ

SCZ0653

50/F

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXX

　

　

+

+

+

SCZ

SCZ0930

60/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY (mosaic)

+

+

+

+

+

SCZ

SCZ1034

76/F

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXX

　

　

+

+

+

SCZ

SCZ1047

60/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY

+

+

+

+

+

SCZ

SCZ1265

70/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY (mosaic)

+

+

+

+

+

SCZ

SCZ1489

55/F

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXX

　

　

+

+

+

SCZ

SCZ1676

47/M

whole chrX

chrX:1-154913754

154 913 754

Dup

　

XXY

+

+

+

+

+

SCZ

SCZ1597

38/F

Xp22.33-p22.31

chrX:6329-8342481

8 336 153

Del

　


　

+

　

　

　

SCZ

SCZ0478

45/M

Xp22.31

chrX:6456312-8095370

1 639 059

Del

Inherited

Recurrent CNV

　

+

　

+

　

SCZ

SCZ1602

27/M

Xp22.31

chrX:6456312-8079237

1 622 926

Dup

　

Recurrent CNV

　

+

+

　

+

SCZ

SCZ0285

60/F

Xp22.31

chrX:6463177-8079237

1 616 061

Dup

　

Recurrent CNV

　

+

+

　

+

SCZ

SCZ0548

58/F

Xp22.31

chrX:6466759-8079237

1 612 479

Del

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ0716

59/F

Xp22.31

chrX:6466759-8079237

1 612 479

Dup

　

Recurrent CNV

　

+

+

　

+

SCZ

SCZ1401

29/F

Xp22.31

chrX:6466759-8079237

1 612 479

Dup

Inherited

Recurrent CNV

　

+

+

　

+

SCZ

SCZ1200

67/F

Xp22.31

chrX:6696984-7724618

1 027 635

Dup

　

Recurrent CNV

　

+

+

　

+

SCZ

SCZ0843

61/M

Xp22.31

chrX:6708609-7850492

1 141 884

Del

　

Recurrent CNV

　

+

　

+

　

SCZ

SCZ0750

53/F

Xp21.1

chrX:31705031-31780508

75 478

Del

　

DMD

+

+

+

+

　

CONT

CON0268

28/M

Xp21.1

chrX:33046861-33074668

27 808

Del

　

DMD

+

+

+

+

　

SCZ

SCZ1350

62/M

Xq22.3-q23

chrX:109211561-114336714

5 125 154

Dup

　


　

　

　

　

　

SCZ

SCZ0186

62/F

Xq28

chrX:154415257-154437478

22 222

Del

　

TMLHE

　

+

+

　

　

SCZ

SCZ0603

41/F

Xq28

chrX:154535668-154840791

305 124

Del

　

TMLHE

　

+

+

　

　

CONT

CON0262

32/M

whole chrY

chrY:1-57772954

57 772 954

Dup

　

XYY

+

　

+

+

+

Abbreviations: ADHD, Attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CONT, control; Del, deletion; Dup, duplication; ID/DD, intellectual disability/developmental delay; SCZ, schizophrenia

Figure S4. Validation of de novo CNVs by TaqMan copy number assays

Eleven de novo CNVs identified in this study were validated by TaqMan copy number assays. Bars indicate copy numbers predicted by TaqMan copy number assays. Samples in red and blue carried aCGH-detected deletions and duplications, respectively. Samples in black carried no aCGH-detected CNVs (copy number = 2). CNTL was used as a calibrator in the assays. Note that SCZ0160 with XXY is male. Abbreviations: CNTL, Control

Table S14. Probabilities for paternity in each trio

Trio ID (Case proband)

Probability of exclusion (PE)

Paternity Index (PI)

Probability of paternity

Trio-01 (SCZ1331)

0.999999308

1515840

0.999999340

Trio-02 (SCZ0459)

0.999998820

7114671

0.999999859

Trio-03 (SCZ0474)

*

-----

876839

0.999998860

Trio-04 (SCZ0094)

0.999999820

11956133

0.999999916

Trio-05 (SCZ0096)

0.999999870

5172454

0.999999807

Trio-06 (SCZ0097)

0.999999900

8656004

0.999999884

Trio-07 (SCZ0110)

0.999999994

123531157

0.999999992

Trio-08 (SCZ0144)

0.999999998

533069968

0.999999998

Trio-09 (SCZ0160)

**

0.999999308

24942654

0.999999960

Trio-10 (SCZ1410)

0.999999990

165287401

0.999999994

Trio-11 (SCZ0801)

0.999999987

254032958

0.999999996

prior probability = 0.5

*: The PE could not be calculated because a paternal mutation was observed at the CSF1PO locus.

**: A maternal mutation was observed at the D19S433 locus.

The PI was calculated according to “Guidance for Standards for Relationship Testing Laboratories (11th Ed)” edited by AABB.

Figure S5. Genome browser view of de novo CNVs with clinical significance

De novo deletions disrupting CACNA1H and MBD5 are displayed in red using the UCSC genome browser. aCGH data are also provided.

X. Clinical characteristics

Data were obtained from 108 of 153 cases with clinically significant CNVs. Treatment resistance was evaluated retrospectively using modified Kane criteria. The criteria included: 1. Drug-refractory condition: At least three periods of treatment with antipsychotics (from at least two chemical classes) at doses >1000 mg per day of chlorpromazine (or equivalent) for 6 weeks with no satisfactory clinical improvement, 2. No stable period of good social and/or occupational functioning.

Table S15. Clinical characteristics of SCZ cases with clinically significant CNVs

Recurrent CNVs

CNVs

Sample ID

Diagnosis, age/sex, ethnicity

Congenital and developmental phenotypes

Education (years)

Age at onset (years old)

Core symptoms

Other neuropsychiatric features

Hospitalizations: number and duration (years)

Treatment

Brain imaging/laboratory tests

Antipsychotics (chlorpromazine equivalent)

Treatment resistance

1q21.1 del

SCZ0503

SCZ, 49/F, Japanese

12 y

41 yo

Auditory hallucinations, persecutory and referential delusions

Depressive symptoms

0, 0

200 mg/day

MRI & laboratory tests: no significant findings

1q21.1 del

SCZ0194

SCZ, 50/F, Japanese

Mild intellectual disability

9 y

29 yo

Delusions, hallucinations

8, 6 y

813 mg/day

+

CT: mild frontal atrophy

1q21.1 del

SCZ0288

SCZ, 74/F, Japanese

16 y

23 yo

Persecutory delusions, disorganized thoughts, disinhibited behavior, avolition, blunted affect

7, 45 y

550 mg/day

1q21.1 del (TAR synd)

SCZ1194

SCZ, 67/M, Japanese

Probable intellectual disability, arrested on a charge of larceny

9 y

23 yo

Hallucinations, delusions, thought disorders, manic symptoms, negative symptoms, cognitive decline

Loss of insight, polydipsia with water intoxication

3, 47 y

1050 mg/day

+

CT: mild diffuse atrophy, bilateral basal ganglia calcification

1q21.1 del (TAR synd)

SCZ0242

SCZ, 66/F, Japanese

12 y

37 yo

Delusions, hallucinations, self-injury, cognitive decline

2, 7 y

1800 mg/day

CT: frontotemporal atrophy, ischemic white matter change

1q21.1 dup (TAR synd)

SCZ0690

SCZ, 36/M, Japanese

Low birth weight (1900 g), unusual behaviors

9 y

26 yo

Auditory hallucinations, persecutory delusions, impulsivity, agitated and violent behavior, negative symptoms

Repeated theft

5, 1 y

1000 mg/day

MRI: periventricular high intensity area on T2-weighted images

2q12.2-q12.3 del

SCZ0208

SCZ, 47/F, Japanese

9 y

30 yo

Persecutory delusions, visual and auditory hallucinations

2, <1 y

1815 mg/day

2q21.1 del

SCZ1092

SCZ, 53/M, Japanese

Developmental delay

9 y

34 yo

Delusions, self-injury behavior

5, 17 y

300 mg/day

3q29 del (de novo)

SCZ0801

SCZ, 55/F, Japanese

Low birth weight (2000 g), patent ductus arteriosus, strabismus, cranial deformation

14 y

20 yo

Persecutory delusions, auditory hallucinations, negative symptoms

Anxiety

2, <1 y

1935 mg/day

+

MRI: punctate high intensity lesions in white matter and pituitary gland enlargement

3q29 del (de novo)

SCZ0094

SCZ, 30/F, Japanese

9 y

15 yo

Auditory hallucinations, persecutory delusions

Anxiety

4, 3 y

1200 mg/day

MRI: frontal atrophy, abnormal EEG

7q11.23 dup

SCZ0088

SCZ, 24/F, Japanese

Possible intellectual disability

14 y

21 yo

Delusions, hallucinations, inappropriate affect

Loss of insight

0, 0

200 mg/day

MRI: no significant findings

13q12.12 del

SCZ1198

SCZ, 63/F, Japanese

12 y

17 yo

Olfactory, somatic, and auditory hallucinations, delusions

Eating disorder

5, 12 y

675 mg/day

15q11.2 del

SCZ0721

SCZ, 48/M, Japanese

16 y

27 yo

Auditory hallucinations, persecutory delusions, negative symptoms

7, 22 y

400 mg/day

CT (50 y): diffuse cortical atrophy

15q11.2 del

SCZ1012

SCZ, 41/M, Japanese

Birth asphyxia, Tic symptoms (11 y)

12 y

15 yo

Delusions of observation and reference, auditory hallucinations, aggressive behavior

Stupor

13, 7 y

1300 mg/day

+

15q11.2 del

SCZ0903

SCZ, 65/F, Japanese

9 y

16 yo

Auditory hallucinations, thought disorders, inappropriate affect, negative symptoms

8, 36 y

1400 mg/day

15q11.2 del

SCZ0931

SCZ, 63/M, Japanese

9 y

33 yo

Auditory hallucinations, disorganized speech and behavior, social withdrawal

3, 19 y

550 mg/day

CT: no significant findings

15q11.2 del

SCZ1054

SCZ, 54/M, Japanese

9 y

14 yo

Auditory hallucinations, persecutory delusions

4, >37 y

627 mg/day

+

15q11.2-q13.1 dup

SCZ1259

SCZ, 42/F, Japanese

Low birth weight (2100 g), Intellectual disability

9 y (special classes)

29 yo

Delusions, disorganized thoughts, irritability, emotional outbursts

Somatic complaints, substupor

9, 2 y

750 mg/day

CT: ventricular enlargement, laboratory tests: normal

15q13.1-q13.2 dup

SCZ0980

SCZ, 68/F, Japanese

9 y

30 yo

Auditory hallucinations, delusions, disorganized and self-injury behavior

5, 25 y

200 mg/day

15q13.1-q13.2 dup (de novo)

SCZ0144

SCZ, 18/F, Japanese

12 y

17 yo

Disorganized behavior, catatonic symptoms

0, 0

0 mg/day


15q13.1-q13.2 del

SCZ0083

SCZ, 25/F, Japanese

14 y

18 yo

Delusions of persecution and observation, thought broadcast

Overeating

6, 1 y

600 mg/day

MRI: no significant findings, abnormal EEG

15q13.3 dup (CHRNA7)

SCZ0732

SCZ, 71/M, Japanese

16 y

27 yo

Delusions (grandiose type), hallucinations, irritability, agitation, negative symptoms

Epilepsy

7, 30 y

500 mg/day

+

CT: diffuse cerebral atrophy, EEG: epileptic discharge


SCZ0863

SCZ, 35/F, Japanese

12 y

20 yo

Reference and persecutory delusions

Eating disorder, possible kleptomania (repeated thefts)

1, <1 y

150 mg/day



SCZ1358

SCZ, 62/M, Japanese

12 y

34 yo

Visual and somatic hallucinations, bizarre delusions, aggressive and violent behavior

Loss of insight

1, 1 y

200 mg/day


SCZ1432

SCZ, 46/F, Japanese

12 y

32 yo

Delusions, hallucinations, disorganized thoughts

Possible kleptomania (repeated thefts), borderline personality disorder, eating disorder

5, <1 y

300 mg/day

CT: mild frontal atrophy

16p12.1 dup

SCZ0921

SZA/SCZ, 49/F, Japanese

Low birth weight

9 y

37 yo

Auditory hallucinations, persecutory delusions, depressive and manic symptoms

5, 8 y

700 mg/day


16p11.2 dup (de novo)

SCZ0110

SCZ, 18/M, Japanese

11 y

18 yo

Persecutory hallucinations

0, 0

0 mg/day


16p11.2 dup

SCZ0818

SCZ, 47/F, Japanese

Intellectual disability


24 yo

Hallucinations, delusions, manic symptoms

2, 17 y

800 mg/day

+

16p11.2 dup

SCZ0819

SCZ, 57/M, Japanese

9 y

22 yo

Visual hallucinations, reference and persecutory delusions, blunted affect

7, 32 y

2803 mg/day

+

CT (57 y): basal ganglia calcification

16p11.2 del (SH2B1)

SCZ0035

SCZ, 31/M, Japanese

12 y

26 yo


2, <1 y

1509 mg/day

　

Brain MRI: pituitary adenoma

17p12 del

SCZ1274

SCZ, 60/F, Japanese

Ocular hypertelorism

12 y

20 yo

Delusions, poor impulse control

11, 39 y

600 mg/day

+

CT: mild frontotemporal atrophy

22q11.21 del

SCZ1130

SCZ, 30/M, Japanese

Atrial septal defect, dysarthria, Intellectual disability

9 y

23 yo

Auditory hallucinations, persecutory and grandiose delusions, negative symptoms

5, 1.5 y

1731 mg/day

+

CT: mild frontal atrophy, left basal ganglia calcification, laboratory tests: hypocalcaemia

22q11.21 del

SCZ1228

SCZ, 52/F, Japanese

Ventricular septal defect, cleft palate, Intellectual disability


36 yo

Auditory hallucinations, persecutory delusions, impulsivity, violent outbursts, negative symptoms

Epilepsy

9, 6 y

340 mg/day

+

CT (54 y): mild frontal atrophy, bilateral basal ganglia calcification, laboratory tests: hypocalcaemia

22q11.21 del

SCZ1231

SZA/SCZ, 36/F, Japanese

Ventricular septal defect, cleft of soft palate, dysarthria, Intellectual disability

12 y

25 yo

Delusions, hallucinations, manic and depressive symptoms, temper outburst, excitement

Hyperventilation

14, 2 y

650 mg/day

CT: frontal atrophy, bilateral basal ganglia calcification

22q11.21 del

SCZ1299

SCZ, 37/F, Japanese

Tetralogy of Fallot, Intellectual disability

9 y

33 yo

Auditory hallucinations, persecutory delusions, psychomotor agitation

　

5, 1 y

1306 mg/day

+


22q11.21 del

SCZ0686

SCZ, 40/F, Japanese

Perinatal asphyxia and hypoxia, tetralogy of Fallot, patent ductus arteriosus, dysarthria, Intellectual disability

12 y

32 yo


Depressive symptoms

1, <1 y

300 mg/day

CT: mild frontal atrophy and right cerebellar atrophy

22q11.21 del (de novo)

SCZ0459

SCZ, 20/F, Japanese

Characteristic face, Intellectual disability

9 y

17 yo

Auditory hallucinations, negative symptoms

2, NA

1027 mg/day

22q11.21 del

SCZ0320

SCZ, 33/F, Japanese

Entropion

12 y

24 yo

Cenesthopathy, auditory hallucinations, persecutory delusions, impulsive and self-destructive behavior

5, <1 y

450 mg/day

22q11.21 del (de novo)

SCZ0096

SCZ, 23/M, Japanese

Cleft palate, Possible intellectual disability

12 y

18 yo

Reference and persecutory delusions

0, 0

1164 mg/day

MRI: cavum septum pellucidum, abnormal EEG

22q11.21 del

SCZ0897

SCZ, 44/F, Japanese

Congenital hearing impairment, Intellectual disability

9 y

19 yo

Persecutory delusions, auditory hallucinations, irritability, agitation

4, 29 y

2459 mg/day

+

Incomplete development of the mastoid cells

22q11.21 del

SCZ0007

SCZ, 59/M, Japanese

Cavernous malformation

9 y

35 yo

Reference and persecutory delusions, hallucinations, avolition, social withdrawal, cognitive decline

Alcohol dependence

0, 0

167 mg/day

22q11.21 del

SCZ1488

SCZ, 41/F, Taiwanese


12 y (special education)

19 yo

Delusions, irritability, aggressive behaviors, negative symptoms

>10, NA

379 mg/day

+


22q11.21 del

SCZ1497

SCZ, 39/M, Taiwanese

Mild developmental delay

9 y

17 yo

Auditory hallucinations, persecutory delusions, bizarre behavior, negative symptoms

4, NA

500 mg/day

+


22q11.21 del

SCZ1592

SCZ, 53/F, Taiwanese

6 y

26 yo

Delusions, hallucinations, disorganized behavior, negative symptoms

>5, NA

400 mg/day

+

CT: calcification in bilateral basal ganglia and a calcified nodule at right frontal horn periventricular region

22q11.21 del

SCZ1645


12 y

34 yo

Hallucinations, negative symptoms

Alcohol dependence

6, NA

400 mg/day

+

22q11.21 del

SCZ1678



9 y

15 yo

Auditory hallucinations, reference and persecutory delusions, disorganized thoughts

>10, NA

850 mg/day

+

22q11.23 dup

SCZ0011

SCZ, 21/F, Japanese

Born as a premature baby

10 y

16 yo

Auditory hallucinations, persecutory delusions, repeated suicide attempts, psychomotor agitation

3, <1 y

700 mg/day

Laboratory tests: no significant findings

22q11.23 dup

SCZ0134

SCZ, 32/M, Japanese

12 y

31 yo

Cenesthetic hallucinations, auditory hallucinations

0, 0

100 mg/day


Xp22.31 (STS) del

SCZ0843

SCZ, 61/M, Japanese

12 y

23 yo

Auditory hallucinations, delusions, thought disorders, negative symptoms, cognitive decline

2, 38 y

1000 mg/day

+

CT (65 y): diffuse cortical atrophy

Xp22.31 (STS) del

SCZ0548

SCZ, 58/F, Japanese

14 y

42 yo

Persecutory delusions, cenesthopathy, auditory hallucinations

Somatic complaints

0, 0

700 mg/day

　

MRI & Blood test: no significant findings, laboratory tests: normal

Xp22.31 (STS) del

SCZ0478

SCZ, 45/M, Japanese

16 y

18 yo

Delusions, hallucinations, negative symptoms

　

3, NA

600 mg/day


Xp22.31 (STS) dup

SCZ1401

SCZ, 29/F, Japanese

12 y

23 yo

Auditory hallucinations, persecutory delusions, bizarre behavior

Major depressive disorder (19 y)

2, <1 y

400 mg/day

MRI & laboratory tests: no significant findings

Xp22.31 (STS) dup

SCZ0716

SCZ, 59/F, Japanese

Borderline intellectual disability

9 y

26 yo

Delusions, hallucinations, disorganized speech and behavior, ne

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