Table S3.

Burden of de novo mutations in 291 midline craniosynostosis trios in known craniosynostosis pathways (Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, retinoic acid)

All genes	Cases, n = 291						Controls, n = 1,789
	Observed		Expected		Enrichment	P	Observed		Expected		Enrichment	P
	n	Rate	n	Rate			n	Rate	n	Rate
Total	36	0.12	20.3	0.07	1.78	0.001	113	0.06	124.6	0.07	0.91	0.86
Synonymous	07	0.02	5.9	0.03	1.19	0.37	34	0.02	36.0	0.03	0.94	0.65
Protein altering	29	0.10	14.4	0.05	2.01	4.7 × 10−4	79	0.04	88.6	0.05	0.89	0.86
Total missense	18	0.06	12.7	0.04	1.42	0.09	72	0.04	78.0	0.04	0.92	0.77
T-mis	010	0.03	9.7	0.03	1.03	0.48	52	0.03	59.4	0.03	0.88	0.85
D-mis	08	0.03	3.0	0.01	2.65	0.01	20	0.01	18.6	0.01	1.08	0.40
LOF	011	0.04	1.7	0.006	6.37	2.1 × 10−6	7	0.003	10.6	0.006	0.66	0.90
Damaging	019	0.07	4.75	0.02	4.00	6.7 × 10−7	27	0.02	29.2	0.02	0.92	0.68

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 genes within this gene set 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.