HAND1

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*HAND1* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Cheng et al., PMID 22032825). At least 3 rare variants (2 missense, 1 frameshift) have been reported in humans. Additional, more frequent missense variants have been reported in blood (Wang et al., PMID 21519287; Cheng et al., PMID: 22032825) and fixed tissue (Reamon-Buettner et al., PMID 18276607; Reamon-Buettner et al., PMID 19586923). Evidence supporting this gene-disease relationship includes case-level data and experimental data. *HAND1* has been noted to be associated with the following disease entities: double-outlet right ventricle with ventricular septal defect, tetralogy of Fallot, and ventricular septal defect (OMIM 602406). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, autosomal dominant *HAND1*-related Congenital Heart Defects. Of note, this gene has also been implicated in abnormalities of placental development and function. These will be assessed separately. Variants in this gene have been reported in at least 3 probands in 3 publications (PMIDs 28112363, 27942761, 22032825), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that *HAND1* is expressed early in mouse and human embryogenesis (PMIDs 7649392, 36563664, 25050861, 28521042, 31341279, 30759401). Loss of *HAND1* resulted in abnormal cardioid formation from human induced pluripotent stem cells (PMIDs 34446706, 34019794). Mouse models demonstrated that cardiac-specific insufficiency and overexpression of *HAND1* both altered cardiac development, particularly the differentiation of ventricular cardiomyocytes (PMIDs 33757801, 17050624, 31286141). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 04/3/23 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: PanelApp Australia