Table S6.

Burden de novo mutations in negative regulators in separated Wnt, BMP, and Ras/ERK signaling pathways in 291 subjects with midline craniosynostosis

Class	Observed		Expected		Enrichment	P value
	n	Rate	n	Rate
Burden of de novo mutations in negative regulators of Wnt signaling
All mutations	8	0.03	3.0	0.01	2.62	0.01
Synonymous	1	0.003	0.9	0.003	1.12	0.59
Protein altering	7	0.02	2.15	0.01	3.25	0.01
Total missense	5	0.02	1.9	0.01	2.63	0.04
D-mis	4	0.01	0.55	0.001	7.25	0.002
LOF	2	0.007	0.25	0.001	8.10	0.03
Damaging	6	0.02	0.80	0.002	7.50	1.8 × 10−4
Burden of de novo mutations in negative regulators of BMP signaling
All mutations	7	0.02	0.94	0.003	7.44	5.7 × 10−5
Synonymous	1	0.003	0.29	0.001	3.42	0.25
Protein altering	6	0.02	0.65	0.002	9.25	6.0 × 10−5
Total missense	3	0.01	0.58	0.002	5.16	0.02
D-mis	2	0.007	0.20	0.001	10.22	0.02
LOF	3	0.01	0.07	0.0002	44.6	4.8 × 10−5
Damaging	5	0.02	0.27	0.001	19.0	8.4 × 10−6
Burden of de novo mutations in negative regulators of Ras/ERK signaling
All mutations	4	0.01	1.81	0.006	2.21	0.11
Synonymous	0	0	—	—	—	—
Protein altering	4	0.01	1.30	0.004	3.09	0.04
Total missense	1	0.003	1.14	0.004	0.88	0.68
D-mis	1	0.003	0.24	0.001	4.24	0.20
LOF	3	0.01	0.16	0.0005	18.7	6.1 × 10−4
Damaging	4	0.01	0.40	0.001	10.1	7.4 × 10−4

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; 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.