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Table 1 Forty-three significantly enriched gene families in the combined de novo paralog-conserved missense and PTV analysis for 10,068 NDD trios. Only enriched gene families significant after applying the Bonferroni significance threshold for testing 5 × 2871 gene families (3.48 × 10−6) are included. Gene names highlighted in red are affected by DNM and the number of DNM is indicated inside the soft brackets. Genes in bold have not previously been reported as significantly enriched in exome-wide ASD, DD, or EPI studies

From: Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Gene families

DNMs expected

DNMs observed

P value

5264 DD patients

3982 ASD patients

822 EPI patients

2087 controls

ARID1B (40), ARID1A (5)

0.96

45

4.28E−58

39

6

0

0

SCN2A (38), SCN1A (18), SCN8A (11), SCN3A (4), SCN11A (2), SCN9A (1), SCN5A, SCN7A, SCN4A, SCN10A

6.16

74

1.77E−52

36

16

22

0

DDX3X (35), DDX3Y

0.49

35

8.94E−52

34

1

0

0

DYRK1A (26), DYRK1B (1)

0.37

27

1.89E−40

21

5

1

0

EP300 (20), CREBBP (16)

1.39

36

8.81E−38

30

5

1

1

KCNQ2 (23), KCNQ3 (7), KCNQ5 (3)

1.14

33

3.09E−36

27

2

4

0

SYNGAP1 (24), DAB2IP, RASAL2

1.33

24

4.35E−22

17

6

1

0

STXBP1 (20), STXBP3 (1), STXBP2

0.88

21

5.93E−22

14

2

5

0

GRIN2B (16), GRIN2A (6), GRIN2C (1), GRIN2D

1.89

23

1.46E−17

17

3

3

0

CTNNB1 (16), JUP (1)

0.79

17

2.27E−17

15

2

0

0

CHD2 (16), CHD1 (3)

1.15

19

4.00E−17

10

8

1

0

PURA (13), PURB

0.41

13

1.13E−15

12

0

1

0

CHD3 (10), CHD4 (6), CHD5 (5)

1.94

21

3.45E−15

19

2

0

0

TCF4 (11), TCF12 (3), TCF3 (2)

0.93

16

5.76E−15

14

2

0

1

CDK13 (14), CDK12

0.66

14

1.71E−14

13

1

0

0

PPP2R5D (16), PPP2R5A (1), PPP2R5B, PPP2R5C, PPP2R5E

1.25

17

3.62E−14

16

1

0

1

WDR45 (11), WDR45B

0.32

11

7.60E−14

9

0

2

0

MEF2C (11), MEF2D (2), MEF2A

0.58

13

7.77E−14

9

2

2

0

EHMT1 (13), EHMT2

0.66

13

3.93E−13

13

0

0

0

FOXP1 (10), FOXP2 (4), FOXP4

0.86

14

6.02E−13

12

2

0

0

FOXG1 (11), FOXQ1, FOXN3, FOXN2

0.39

11

6.36E−13

7

1

3

0

CHD8 (12), CHD7 (7), CHD9 (1)

2.30

20

7.73E−13

11

9

0

0

CSNK2A1 (12), CSNK2A3, CSNK2A2

0.63

12

5.00E−12

10

1

1

0

CACNA1E (10), CACNA1A (9), CACNA1B (1)

2.72

20

1.53E−11

13

1

6

0

HDAC8 (9), HDAC3 (2), HDAC1 (1), HDAC2

0.83

12

1.06E−10

11

0

1

0

GNAO1 (7), GNAI1 (7), GNAZ (1), GNA11 (1), GNA14, GNAI3, GNAT2, GNAT3, GNAT1, GNAI2, GNA15, GNAQ

1.82

16

1.31E−10

13

2

1

0

CASK (8), DLG4 (6), DLG2 (1), DLG1, DLG3

1.58

15

1.67E−10

12

1

2

0

GATAD2B (10), GATAD2A

0.65

10

2.10E−09

10

0

0

0

MED13L (12), MED13 (2)

1.68

14

3.47E−09

10

4

0

0

TBL1XR1 (9), TBL1Y, TBL1X

0.52

9

5.01E−09

7

2

0

0

PHIP (10), BRWD3 (2)

1.46

13

5.64E−09

10

2

1

0

CTCF (9), CTCFL

0.56

9

9.00E−09

7

2

0

0

RAB11A (3), RAB2A (2), RAB11B (2), RAB14 (2), RAB19 (1), RAB43 (1), RAB39A, RAB25, RAB4B, RAB39B, RAB4A, RAB30, RAB2B

1.01

11

1.14E−08

9

2

0

0

GABRB3 (8), GABRB2 (3), GLRA2 (1), GABRB1 (2), GLRB (1), GLRA1, GABRR1, GABRD, GABRR3, GABRP, GLRA4, GABRQ, GABRR2, GLRA3

2.35

15

3.15E−08

7

4

4

0

TCF20 (9), RAI1 (3)

1.40

12

3.33E−08

11

1

0

1

NFIX (6), NFIA (2), NFIB (2), NFIC

0.90

10

4.31E−08

8

2

0

1

USP9X (10), USP24 (1), USP9Y

1.18

11

5.29E−08

9

2

0

0

SATB2 (9), SATB1

0.75

9

1.04E−07

9

0

0

0

HECW2 (9), HECW1 (1)

1.04

10

1.61E−07

8

1

1

0

SOX11 (4), SOX4 (3), SOX9 (1), SOX10 (1), SOX17, SOX1, SOX8, SOX7

0.82

9

2.21E−07

9

0

0

0

ZBTB18 (6), ZBTB3

0.28

6

5.43E−07

6

0

0

0

TCF7L2 (6), TCF7L1 (1)

0.53

7

1.48E−06

4

3

0

0

TBR1 (6), EOMES

0.35

6

2.01E−06

1

5

0

0