Table 1.

Signaling Factors Involved in Both Ventricular Wall and Ventricular Conduction System Development

LOF phenotype			GOF phenotype
Factor	VCS	Wall Formation	VCS	Human Mutations	Wall Formation
Notch	Anatomy: Intact His/Purkinje System. AV nodal hypoplasia. EKG: Unchanged QRS. Shortened PR. EGM: Shortened AH. Unchanged HV.39	Poorly formed trabeculae and myocardial structure.34	Reprogramming of ventricular myocardium towards a Purkinje-like phenotype.39	Hypertrabeculation and noncompaction.38	Hey2 variant associated with Brugada Syndrome. Increased likelihood of SCD and ventricular arrhythmias.61
Id2	Anatomy: Absence of a discrete His bundle and abnormal LBB. EKG: Widened QRS. LBBB pattern. EGM: Broad and split ventricular spike.41	Ventricular wall hypoplasia and poorly developed compact layer.42	Unknown	Unknown	Unknown
Irx3	Anatomy: Abnormal embryonic differentiation. Postnatal VCS hypoplasia and dysregulated maturation. EKG: Widened QRS. BBB pattern. EGM: Normal AH. Prolonged HV.11,43	Structurally normal but significantly increased proliferation of working myocardium.11	Unknown	Unknown	Missense IRX3 mutations associated with idiopathic VT and a propensity for NSVT with exercise.44
Nkx2.5	Anatomy: Atrophy of AV node and His bundle. Haploinsufficiency results in reduced number of Cx40+ Purkinje Fiber cells. EKG: Progressive AV block. Prolonged QRS. EGM: Prolonged AH. Normal HV with haploinsufficiency.46, 47, 48	Hypertrabeculation and myocardial overgrowth.46	Unknown	Unknown	NKX2.5 haploinsufficiency associated with SCD and arrhythmias including VT.49
BMP10	Unknown	Ventricular wall hypoplasia with absence of trabeculae.50	Reduced number of Cx40+ PFs.46	Increased proliferation of working myocardium.46	Unknown
Hopx	Anatomy: Dysfunctional VCS in the setting of decreased Cx40 expression. EKG: Prolonged QRS. EGM: Trending prolongation of AH. Prolonged HV.52	Myocardial overgrowth and hyperplasia.51	Unknown	Unknown	Unknown