Table 2 Description of novel mutations.

Gene	Substitution	Number of affected people	Parental analysis	Number of negative controls tested		Pathogenic mutation affecting the same residue	Interspecies conservation†	PolyPhen prediction	Conclusion
				This study	Literature*
BRAF	T241P	1	De novo	200	155		Yes	Probably damaging	Mutation
	Q262R	1	Absent in mother	200	155		S in Drosophila	Benign	Mutation (probable)
	G464R	1	–	200			Yes	Probably damaging	Mutation (probable)
	E501V	1	–	200	105	E501G, E501K	Yes	Probably damaging	Mutation (probable)
	N581K	1	De novo	–	–		Yes	Probably damaging	Mutation
MEK1	E44G	1	Mutated in asymptomatic mother	200	–		T in Drosophila	Possibly damaging	Possible rare polymorphism
	T55P	1	–	200	–		S in Drosophila	Possibly damaging	Mutation (probable)
	D67N	3	De novo (2 patients)	200	–		Yes	Benign	Mutation
MEK2	L46_E55del	1	De novo	200	50		–	–	Mutation
	K61T	1	De novo	200	50	K61E	Yes	Benign	Mutation
	A62P	2	De novo (2 patients)	200	50		E in C elegans	Benign	Mutation
KRAS	K5E	1	–	200	>500		Yes	Probably damaging	Mutation
	G12S	1	Absent in mother	200	>500	Somatic G12S	Yes	Benign	Mutation

*BRAF, MEK1 and MEK2 negative controls were tested in Niihori et al¹³ Norumi et al.²⁰

†When orthologous genes were present, the human sequence was compared with that of Mus musculus, Rattus norvegicus, Danio rerio, Drosophila melanogaster and Caenorhabditiselegans.