Background
Methods
Study samples
Targeted sequencing of the ACGC
Categories | Phase I | Phase II | Total | ||
---|---|---|---|---|---|
Stage 1 | Stage 2 | Total | |||
Probands subjected to sequencing | 1647 (1086) | 851 (735) | 622 (455) | 1473 (1190) | 3120 (2276) |
Probands after QC | 1543 (1045) | 784 (672) | 599 (437) | 1383 (1109) | 2926 (2154) |
Targeted gene numbers | 211 | 211 | 85 | – | – |
Targeted gene numbers after QC | 187 | 187 | 85 | – | – |
Quality control and variant calling
Variant validation and microsatellite analysis
Statistical analyses
Results
Mutation discovery
Recurrent new mutations and candidate genes
Gene | ACGC (n = 2145) | ACGC+SSC+ASC (n = 6107) | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Phase-I | Phase-II | All | CH model | denovolyzeR | LGD | MIS | All | CH model | denovolyzeR | ||||||||
LGD | MIS | LGD | MIS | LGD | MIS | LGD_q | prot_q | LGD_q | prot_q | LGD_q | prot_q | LGD_q | prot_q | ||||
SCN2A
†
| 6 | 4 | 5 | 9 | 11 | 13 |
3.68E−25
|
1.23E−40
|
4.21E−18
|
1.05E−29
| 15 | 21 | 36 |
7.77E−28
|
2.23E−49
|
3.52E-22
|
3.35E-42
|
CHD8
†
| 3 | 1 | 2 | 1 | 5 | 2 |
3.18E−09
|
7.56E−08
|
5.40E−07
|
1.68E−04
| 14 | 4 | 18 |
7.49E−25
|
7.45E−18
|
3.52E−22
|
1.19E−13
|
MECP2
†
| 1 | 3 | 2 | 1 | 3 | 4 |
1.00E−06
|
1.12E−11
|
1.78E−05
|
4.12E−08
| 3 | 5 | 8 |
6.26E−04
|
1.33E−08
|
1.78E−03
|
1.42E−06
|
DYRK1A
†
| 1 | 1 | 2 | 0 | 3 | 1 |
1.51E−05
|
2.78E−04
|
5.92E−05
|
2.75E−03
| 8 | 1 | 9 |
3.78E−13
|
2.51E−07
|
1.31E−13
|
4.23E−07
|
ASXL3
†
| 0 | 1 | 3 | 1 | 3 | 2 |
7.28E−04
|
5.62E−03
|
1.82E−04
|
4.29E−03
| 5 | 2 | 7 |
6.33E−04
| 0.894 |
6.03E−06
|
0.0200
|
WAC
†
| 0 | 0 | 2 | 0 | 2 | 0 |
9.05E−04
|
0.0311
|
5.14E−03
| 0.2322 | 4 | 0 | 4 |
2.12E−05
| 0.0532 |
6.57E−05
| 0.1384 |
FOXP1
†
| 0 | 0 | 2 | 1 | 2 | 1 |
1.04E−03
|
3.46E−03
|
0.0103
|
0.0285
| 4 | 1 | 5 |
3.36E−05
|
0.014
|
3.81E−04
|
0.0235
|
CTTNBP2
| 0 | 1 | 2 | 0 | 2 | 1 |
4.69E−03
|
0.0189
|
0.0226
| 0.2162 | 3 | 1 | 4 |
0.0331
| 1 | 0.1072 | 1 |
TNRC6B
†
| 0 | 0 | 2 | 0 | 2 | 0 |
7.00E−03
| 0.2549 |
0.0158
| 0.5818 | 4 | 0 | 4 |
1.97E−03
| 1 |
1.17E−03
| 1 |
MED13L
†
| 1 | 0 | 1 | 0 | 2 | 0 |
7.00E−03
| 0.2549 |
0.0386
| 0.9485 | 4 | 1 | 5 |
1.97E−03
| 0.9197 |
9.40E−03
| 1 |
CDKL5
†
| 1 | 0 | 1 | 0 | 2 | 0 |
8.26E−03
| 0.2732 |
7.14E−03
| 0.3409 | 2 | 1 | 3 | 1 | 1 | 0.5527 | 1 |
DSCAM
†
| 2 | 0 | 0 | 1 | 2 | 1 |
0.0130
| 0.0770 |
0.0226
| 0.3035 | 6 | 2 | 8 |
1.03E−05
|
0.0272
|
1.55E−06
|
0.0135
|
ZNF292
| 1 | 0 | 1 | 0 | 2 | 0 |
0.0139
| 0.6051 |
0.0158
| 0.8299 | 3 | 2 | 5 | 0.2763 | 1 | 0.0508 | 1 |
POGZ
†
| 1 | 1 | 0 | 0 | 1 | 1 | 0.0507 |
0.0153
| 0.3864 | 0.5818 | 4 | 4 | 8 |
2.40E−06
|
1.84E−09
|
3.48E−03
|
7.13E−04
|
WDFY3
| 1 | 1 | 0 | 2 | 1 | 3 | 0.2966 |
0.0153
| 0.7292 | 0.2736 | 3 | 7 | 10 | 0.2778 |
7.21E−04
| 1 |
5.44E−03
|
NAA15
†
| 0 | 0 | 1 | 1 | 1 | 1 | 0.0851 |
0.0228
| 0.3452 | 0.3025 | 2 | 2 | 4 | 0.1747 |
0.0287
| 1 | 0.4185 |
CUL3
| 1 | 0 | 0 | 1 | 1 | 1 | 0.1056 |
0.0446
| 0.3825 | 0.3035 | 2 | 1 | 3 | 0.2778 | 1 | 1 | 1 |
STXBP1
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.1056 | 0.6051 | 0.3267 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 |
ADNP
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.1314 | 0.9222 | 0.2294 | 1 | 5 | 0 | 5 |
2.40E−06
| 0.0764 |
4.55E−07
| 0.0669 |
DDX3X
†
| 0 | 1 | 1 | 0 | 1 | 1 | 0.1335 | 0.0871 | 0.2367 | 0.2989 | 2 | 1 | 3 | 0.7186 | 1 | 0.4989 | 1 |
RALGAPB
| 0 | 0 | 1 | 1 | 1 | 1 | 0.1335 | 0.0815 | 0.3267 | 0.5816 | 2 | 1 | 3 | 0.6237 | 1 | 1 | 1 |
GIGYF2
| 1 | 1 | 0 | 0 | 1 | 1 | 0.1335 | 0.0770 | 0.6428 | 0.5818 | 2 | 3 | 5 | 0.7186 |
0.0363
| 1 | 0.5211 |
NCKAP1
| 1 | 0 | 0 | 0 | 1 | 0 | 0.1335 | 0.9135 | 0.5383 | 1 | 3 | 0 | 3 |
0.0206
| 1 | 0.4100 | 1 |
GRIN2B
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.1359 | 1 | 0.2367 | 1 | 4 | 0 | 4 |
4.61E−04
| 1 |
1.17E−04
| 1 |
MYT1L
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.1717 | 1 | 0.2294 | 1 | 2 | 2 | 4 | 1 | 1 | 0.4100 | 1 |
SHANK2
| 0 | 0 | 1 | 0 | 1 | 0 | 0.2017 | 1 | 0.3267 | 1 | 2 | 1 | 3 | 1 | 1 | 1 | 1 |
SYNGAP1
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.2966 | 1 | 0.3154 | 1 | 6 | 3 | 9 |
1.84E−05
|
0.0168
|
8.04E−08
|
8.79E−05
|
PHIP
†
| 1 | 0 | 0 | 0 | 1 | 0 | 0.2966 | 1 | 0.5095 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 |
CHD2
†
| 0 | 0 | 1 | 1 | 1 | 1 | 0.3536 | 0.9217 | 0.5095 | 0.7736 | 4 | 4 | 8 |
0.0331
| 0.5391 |
0.0125
|
3.31E−03
|
SHANK1
| 1 | 0 | 0 | 0 | 1 | 0 | 0.3536 | 1 | 0.3267 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 |
DOCK8
| 1 | 0 | 0 | 0 | 1 | 0 | 0.4837 | 1 | 0.3267 | 1 | 2 | 0 | 2 | 1 | 1 | 1 | 1 |
ANK2
| 0 | 1 | 1 | 0 | 1 | 1 | 0.7356 | 1 | 0.6639 | 1 | 5 | 4 | 9 | 0.0587 | 1 |
2.54E−03
|
0.0396
|
ASH1L
†
| 0 | 1 | 0 | 1 | 0 | 2 | 1 | 0.2732 | 1 | 1 | 3 | 2 | 5 | 0.0825 | 1 | 0.5350 | 1 |
RIMS1
| 0 | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 2 | 1 | 3 | 0.7186 | 1 | 1 | 1 |
TSC2
†
| 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 4 | 4 | 1 | 1 | 1 | 1 |
KMT2C
| 0 | 1 | 0 | 1 | 0 | 2 | 1 | 1 | 1 | 1 | 1 | 4 | 5 | 1 | 1 | 1 | 1 |
ITPR1
| 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 3 | 3 | 1 | 1 | 1 | 1 |
WHSC1
| 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0.9499 | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 |
Clinical evaluation of ASD-relevant mutations
Multiple DNMs in ASD patients
Inheritance of potential high-risk mutations
Sample ID | Mutation | Sex | Age | WAIS/WISC | BAPQ | HC (Z-score) | Height | Weight | BMI | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Verbal | Nonverbal | Full-scale | Aloof | Pragmatic | Rigid | Overall | ||||||||
GX0347.p1 | p.R1935* | M | 62 M | 31 | 26 | 21 | – | – | – | – | 52.5(1.15) | 126.2 | 25 | 15.6 |
GX0347.mo | p.R1935* | F | 29 Y | 88 | 75 | 80 | 3 | 2.79 | 3.54 | 3.11 | 57.3(2.48) | 161.7 | 67.5 | 25.8 |
GX0540.p1 | p.N855Tfs*14 | F | 163 M | – | – | 36 | – | – | – | – | 58.5(3.58) | 161.5 | 84 | 32.2 |
GX0540.fa | p.N855Tfs*14 | M | 42 Y | 95 | 79 | 87 | 2.88 | 3.21 | 3.88 | 3.32 | 58.7(1.53) | 167.8 | 71 | 25.22 |
HN0277.p1 | p.E2011Dfs*32 | F | 59 M | – | – | – | – | – | – | – | 53(2.26) | 112 | 20 | 15.9 |
HN0277.mo | p.E2011Dfs*32 | F | 26 Y | 88 | 75 | 80 | 2.79 | 2.88 | 3.92 | 3.19 | – | – | – | – |