TABLE I.

Molecular findings in patients with holoprosencephaly

	Affected Gene	Inheritance	Sequence Variant	Domain	Predicted effect	References	Comments
Patients 1 and 2	SHH	Familial	c.588_602del (p.Gly197_Gly201 del)	C-terminus	In-frame deletion including autocleavage site (Cys 198), resulting in possible alteration of protein processing		Patient 2 is the mother of Patient 1
Patient 3	SIX3	de novo	c.769C>T (p.Arg257Trp)	Homeodomain	Intermediate loss-of-function	[Domené et al., 2008]	-
Patient 4	SHH	de novo	46, XX, del(7)(q36). arr cgh 7q36.1q36.3(149, 597,103–158,739,800)×1 including SHH	Whole gene	Whole gene deletions have previously been described to cause severe holoprosencephaly; however, incomplete penetrance and variable expressivity are high for this particular locus	[Solomon et al., 2010b]	-
Patients 5 and 6	SHH	Familial	c.1051C>T (p.Gln351*)	C-terminus	Truncation of C-terminus, resulting in possible alteration of protein processing.	[Roessler et al., 2009a]	Patient 6 is the mother of Patient 5
Patient 7	FGF8	Familial	c.686C>T (p.Thr229Met)	C-terminus	Hypomorphic mutation related with midline defects, including HPE, and idiopathic hypogonadotropic hypogonadism	[Arauz et al., 2010; Falardeau et al., 2008]	-
Patients 8 and 9	SIX3	Familial	c.743_745del (p.Thr248_Gln249delinsLys)	Homeodomain	Possible loss-of-function	[Lacbawan et al., 2009]	Patient 9 is the mother of Patient 8
Patient 10	ZIC2	de novo	c.612del (p.Tyr205ThrFS* 13)	5′ to Homeodomain	Predicted null due to absence of the homeodomain	[Roessler et al., 2009b]	-