Background: A clinician’s ability to identify patients with potentially worse outcomes based on genotype can greatly improve personalized tailoring of congenital heart disease (CHD) treatment. The cellular or molecular basis of CHDs can lead to insight into CHD origin as well as the possibility of progressive dynamic complications allowing for risk stratification. Despite advances in the genetic basis of CHD, the etiology for the majority of children who have different CHD defects remains largely unknown. This paper examines the genes reported thus far which have a high degree of association with different CHD defects and implications for future research. 

Methods: NCBI Gene Bank, LILACS, PubMed, MEDLINE, SciELO, and ScienceDirect were included to identify1644 relevant papers on genetic variants in CHD published between 1998 and 2022 with the majority (n=839) published in the last seven years. Gene variants were included if genotype-phenotype association results were found in >=2 studies. The gene variants reported in a single study and not confirmed by another independent study were excluded.

Results: In our analysis of 1644 research publications on CHD defects, we report genes where the genotype-phenotype association was shown in >=2 studies.
(i) Aortic Coarctation: MYH7, del22q11.2, del1p36, del6q25.1, NKX 2.5, NKX2.6, GATA6, TBX1
(ii) Aortic Root Dilatation: del22q11.2, del1p36 
(iii) ASD: GATA4, TBX5, MYHC, ACTC, MYH6, MYH7, TBX20, Trisomy18, del1p36, del6q25.1, CRELD1, TLL1, CITED2, GATA6  
(iv) AVSD: NKX2.5, CRELD1, GATA4, TBX5, del6q25.1 GJA1, GATA6, NR2F2
(v) Bicuspid Aortic Valve: Notch1, MYH7, TBX20, SMAD6, ROBO4
(vi) TGA: CFC1, ZIC3, NKX2.5, PROSIT240
(vii) Double-outlet Right Ventricle: CFC1, NKX2.5 , TBX20, CFC1
(viii) Ebstein Anamoly: MYH7, GATA4, NKX2.5
(ix) Heterotaxy: GATA4, ZIC3, CFC1, ACVR2B, LEFTYA
(x) HLHS: MYH6, Notch1, RBFOX2, NKX2.5, TBX5, del6q25.1, GJA1 
(xi) Left Ventricular Non Compaction: del22q11.2, del1p36
(xii) PDA: TBX5, MYH11, Trisomy18, del1p36, del6q25.1, PRDM6, ACTA2, R187
(xiii) Polyvalvular disease: Trisomy18, del6q25.1
(xiv) Premature ventricular contraction: del6q25.1
(xv) Pulmonary Artery Hypoplasia: MYH7
(xvi) TOF: ZFPM2, NKX2.5, JAG1, GATA4, TBX5, TBX20, del22q11.2, del1p36, del6q25.1, GATA6, TBX1
(xvii) Thoracic Aortic Aneurysms: TBX20
(xviii) Total Anomalous Pulmonary Venous Return: TBX5
(xix) Truncus Arteriosus: TBX5, TBX20, del22q11.2, NKX2.6, GATA6, TBX1, ACTA2, R187
(xx) Valvular Dysplasia: NKX2.5, TBX20
(xxi) VSD: NKX2.5, GATA4, TBX5, MYH7, Trisomy18, del22q11.2, del1p36l, del6q25.1, CITED2, ETS1

Conclusions: Molecular mechanisms are an active area of research in CHD. Further advances will inform personalized medicine in CHD in terms of risk stratification, management, and treatment. The disease prognosis can be affected by changes in mutations; and by growing understanding of associations of the gene variants with different static and dynamic progressive phenotype changes, genetic knowledge can be applied to clinical decision-making for more CHD patients.