Table 1.

Summary of known cardiac-related phenotypes in gain-of-function and loss-of-function analysis for Hand factors

Gene	Cardiovascular phenotypes	Reference
Hand1	Mouse: Systemic Hand1 KO display extraembryonic and placental & vascular defects. Dies at E9-9.5.	[15, 30, 40]
	Conditional knockout using cardiac-specific Cre drivers show hypoplastic left ventricle and clear gene dosage with Hand2.	[29]
	Neural crest inactivation of Hand1 displays no observable phenotypes; however, Hand2 gene dosage effects are observed.	[1]
	Hand1 inducible gain-of-function during embryogenesis increases cardiomyocyte proliferation. Expression via knockin to Mlc2v inhibited septum formation expanded ventricular size.	[46]
	Hand1 gain-of-function in adult heart predisposes mice to arrhythmias.	[3, 41]
Hand2	Systemic Hand2 KO mice display right reduction in right ventricle and vascular defects. Dies at E9.5-E10.0	[44]
	Cardiac knockout of Hand2 using cTnt-Cre phenocopy a reduction in right ventricle. Hand1 gene dosage effects not evaluated	[31]
	Neural crest inactivation of Hand2 display OFT defects. Hand1 gene dosage effects not evaluated	[31]
	Chick: Antisense knockdown of either Hand1 or 2 has no observable phenotype; however, knockdown of both genes results in defective heart development	[43]
	Fish: The single Hand gene as two mutant alleles termed Hands off these fish display in lower number of myocardial cell precursors and do not maintain Tbx5 expression within the myocardium.	[48]
	Fly: Drosophila Hand semi lethal larva—lymph glands missing. Adult flies display abnormal dorsal vessel disorganized musculature and reduced function.	[25]
Twist1	Mouse: Twist1 loss-of-function exhibits adhesion and emigration defects in cardiac neural crest cells marked by expression of Hand1 and Hand2	[47]