Table S4.

Burden of de novo mutations in 291 midline craniosynostosis trios in regulators of Wnt, BMP, and Ras/ERK signaling

Regulators	Cases, n = 291						Controls, n = 1,789
	Observed		Expected		Enrichment	P	Observed		Expected		Enrichment	P
	n	Rate	n	Rate			n	Rate	n	Rate
All regulators of Wnt, BMP, and Ras-ERK signal transduction
Total	33	0.11	16.8	0.06	1.96	3.2 × 10−4	95	0.05	103.5	0.06	0.92	0.81
Synonymous	6	0.02	4.86	0.02	1.23	0.36	29	0.02	29.9	0.02	0.97	0.59
Protein altering	27	0.09	12.0	0.04	2.25	1.3 × 10−4	66	0.04	73.6	0.04	0.90	0.83
Total missense	16	0.05	10.5	0.04	1.52	0.07	60	0.03	64.8	0.04	0.93	0.74
T-mis	8	0.03	7.96	0.03	1.01	0.49	44	0.02	49.2	0.03	0.89	0.70
D-mis	8	0.03	2.54	0.01	3.15	0.005	16	0.01	15.6	0.01	1.02	0.50
LOF	11	0.04	1.43	0.005	7.66	3.6 × 10−7	6	0.003	8.83	0.005	0.68	0.87
Damaging	19	0.07	3.97	0.01	4.77	4.8 × 10−8	22	0.01	24.5	0.01	0.90	0.72
Negative regulators of Wnt, BMP, and Ras-ERK signal transduction
Total	19	0.07	5.46	0.02	3.48	4.9 × 10−6	31	0.02	33.6	0.02	0.92	0.69
Synonymous	2	0.007	1.60	0.005	1.26	0.47	12	0.007	9.8	0.005	1.22	0.28
Protein altering	17	0.058	3.87	0.013	4.39	7.35 × 10−7	19	0.011	23.8	0.013	0.80	0.86
Total missense	9	0.031	3.42	0.012	2.63	8.56 × 10−3	17	0.010	21.0	0.012	0.81	0.84
T-mis	2	0.007	2.50	0.009	0.80	0.54	14	0.008	15.4	0.009	0.97	0.55
D-mis	7	0.024	0.92	0.003	7.65	4.82 × 10−5	3	0.002	5.6	0.003	0.53	0.92
LOF	8	0.027	0.45	0.002	17.6	3.04 × 10−8	2	0.001	2.8	0.002	0.72	0.77
Damaging	15	0.052	1.37	0.005	10.9	2.40 × 10−11	5	0.003	8.42	0.005	0.59	0.92
Positive regulators of Wnt, BMP, and Ras-ERK signal transduction
Total	14	0.05	11.4	0.04	1.23	0.26	64	0.04	70.0	0.04	0.91	0.78
Synonymous	4	0.01	3.27	0.01	1.22	0.41	17	0.01	20.1	0.01	0.84	0.79
Protein altering	10	0.03	8.12	0.03	1.23	0.30	47	0.03	49.9	0.03	0.94	0.68
Total missense	7	0.02	7.14	0.02	0.98	0.57	43	0.02	43.9	0.02	0.98	0.57
T-mis	6	0.02	5.52	0.02	1.09	0.46	30	0.02	33.9	0.02	0.88	0.80
D-mis	1	0.003	1.62	0.006	0.61	0.80	13	0.007	10.0	0.006	1.30	0.21
LOF	3	0.01	0.98	0.003	3.05	0.07	4	0.002	6.04	0.003	0.66	0.85
Damaging	4	0.01	2.61	0.009	1.53	0.26	17	0.01	16.0	0.009	1.06	0.44

Damaging and tolerated missense called by MetaSVM (D-mis and T-mis, respectively). LOF denotes premature termination, frameshift, or splice-site mutation; damaging denotes LOF + D-mis; n, number of de novo mutations in 291 subjects or 1,789 controls; rate, number of de novo mutations per subject. P values represent the upper tail of the Poisson probability density function. Bold text indicates significant P values.