Background: Advanced molecular mechanism research incorporated with multidisciplinary collaborations on congenital heart disease has prompted new insight into its cause, development, and outcomes. Summary: This literature review aims to comprehensively examine the genetic molecular mechanisms of congenital heart disease and explain current prospects and challenges in this field. Through a systematic exploration of etiology, embryology, clinical outcomes, algorithms, and ethics, we seek to shed light on the path toward improved diagnostics, treatments, and outcomes for patients. Key Message: Collaboration among genetic researchers, clinicians, data scientists, ethicists, and policymakers is crucial to address challenges and translate research findings into tangible benefits for CHD patients.

1.
Bellsham-Revell
H
,
Burch
M
.
Congenital heart disease in infancy and childhood
.
Medicine
.
2022
;
50
(
9
):
579
86
.
2.
Wu
W
,
He
J
,
Shao
X
.
Incidence and mortality trend of congenital heart disease at the global, regional, and national level, 1990-2017
.
Medicine
.
2020
;
99
(
23
):
e20593
.
3.
Paç
FA
,
Aydemir
MM
,
Eriş
D
,
Sayin
S
,
Aladağ
P
,
Paç
M
.
Prevalence, clinical features and complications of grown-up congenital heart disease: single-center clinical experience
.
Prog Cardiol
.
2022
;
2
:
1
10
.
4.
Morton
SU
,
Shimamura
A
,
Newburger
PE
,
Opotowsky
AR
,
Quiat
D
,
Pereira
AC
, et al
.
Association of damaging variants in genes with increased cancer risk among patients with congenital heart disease
.
JAMA Cardiol
.
2021
;
6
(
4
):
457
62
.
5.
Gelb
BD
.
Prospects for precision genetic medicine in congenital heart disease
.
Curr Opin Genet Dev
.
2022
;
77
:
101983
.
6.
Whittemore
R
,
Hobbins
JC
,
Engle
MA
.
Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease
.
Am J Cardiol
.
1982
;
50
(
3
):
641
51
.
7.
Diab
NS
,
Barish
S
,
Dong
W
,
Zhao
S
,
Allington
G
,
Yu
X
, et al
.
Molecular genetics and complex inheritance of congenital heart disease
.
Genes
.
2021
;
12
(
7
):
1020
.
8.
Goldmuntz
E
,
Geiger
E
,
Benson
DW
.
NKX2.5 mutations in patients with tetralogy of Fallot
.
Circulation
.
2001
;
104
(
21
):
2565
8
.
9.
Sanchez-Castro
M
,
Eldjouzi
H
,
Charpentier
E
,
Busson
PF
,
Hauet
Q
,
Lindenbaum
P
, et al
.
Search for rare copy-number variants in congenital heart defects identifies novel candidate genes and a potential role for FOXC1 in patients with coarctation of the aorta
.
Circ Cardiovasc Genet
.
2016
;
9
(
1
):
86
94
.
10.
Guida
V
,
Sparascio
FP
,
Bernardini
L
,
Pancheri
F
,
Melis
D
,
Cocciadiferro
D
, et al
.
Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects
.
Clin Genet
.
2021
;
100
(
3
):
268
79
.
11.
Reuter
MS
,
Chaturvedi
RR
,
Liston
E
,
Manshaei
R
,
Aul
RB
,
Bowdin
S
, et al
.
The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease
.
Genet Med
.
2020
;
22
(
6
):
1015
24
.
12.
Granados-Riveron
JT
,
Pope
M
,
Bu'lock
FA
,
Thornborough
C
,
Eason
J
,
Setchfield
K
, et al
.
Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations
.
Congenit Heart Dis
.
2012
;
7
(
2
):
151
9
.
13.
Bruneau
BG
.
The developmental genetics of congenital heart disease
.
Nature
.
2008
;
451
(
7181
):
943
8
.
14.
Verhoeven
MC
,
Haase
C
,
Christoffels
VM
,
Weidinger
G
,
Bakkers
J
.
Wnt signaling regulates atrioventricular canal formation upstream of BMP and Tbx2
.
Birth Defects Res A Clin Mol Teratol
.
2011
;
91
(
6
):
435
40
.
15.
Chi
C
,
Knight
WE
,
Riching
AS
,
Zhang
Z
,
Tatavosian
R
,
Zhuang
Y
, et al
.
Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling
.
iScience
.
2023
;
26
(
7
):
107012
.
16.
Aguayo-Gomez
A
,
Arteaga-Vazquez
J
,
Svyryd
Y
,
Calderón-Colmenero
J
,
Zamora-González
C
,
Vargas-Alarcón
G
, et al
.
Identification of copy number variations in isolated tetralogy of Fallot
.
Pediatr Cardiol
.
2015
;
36
(
8
):
1642
6
.
17.
Postma
AV
,
Bezzina
CR
,
Christoffels
VM
.
Genetics of congenital heart disease: the contribution of the noncoding regulatory genome
.
J Hum Genet
.
2016
;
61
(
1
):
13
9
.
18.
Zhang
TN
,
Wu
QJ
,
Liu
YS
,
Lv
JL
,
Sun
H
,
Chang
Q
, et al
.
Environmental risk factors and congenital heart disease: an umbrella review of 165 systematic reviews and meta-analyses with more than 120 million participants
.
Front Cardiovasc Med
.
2021
;
8
:
640729
.
19.
Li
AH
,
Hanchard
NA
,
Furthner
D
,
Fernbach
S
,
Azamian
M
,
Nicosia
A
, et al
.
Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns
.
Genome Med
.
2017
;
9
(
1
):
95
.
20.
Barlow
GM
,
Chen
XN
,
Shi
ZY
,
Lyons
GE
,
Kurnit
DM
,
Celle
L
, et al
.
Down syndrome congenital heart disease: a narrowed region and a candidate gene
.
Genet Med
.
2001
;
3
(
2
):
91
101
.
21.
Pelleri
MC
,
Gennari
E
,
Locatelli
C
,
Piovesan
A
,
Caracausi
M
,
Antonaros
F
, et al
.
Genotype-phenotype correlation for congenital heart disease in Down syndrome through analysis of partial trisomy 21 cases
.
Genomics
.
2017
;
109
(
5–6
):
391
400
.
22.
Urban
Z
,
Riazi
S
,
Seidl
TL
,
Katahira
J
,
Smoot
LB
,
Chitayat
D
, et al
.
Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome
.
Am J Hum Genet
.
2002
;
71
(
1
):
30
44
.
23.
Yuan
SM
.
Congenital heart defects in Williams syndrome
.
Turk J Pediatr
.
2017
;
59
(
3
):
225
32
.
24.
Zhou
J
,
Wu
Y
,
Xu
X
,
Zhang
Y
,
Zhang
X
,
Chen
H
, et al
.
Identification and characterization of novel elastin gene mutations in eleven families with supravalvular aortic stenosis
.
Front Genet
.
2022
;
13
:
1059640
.
25.
Tomita-Mitchell
A
,
Stamm
KD
,
Mahnke
DK
,
Kim
MS
,
Hidestrand
PM
,
Liang
HL
, et al
.
Impact of MYH6 variants in hypoplastic left heart syndrome
.
Physiol Genomics
.
2016
;
48
(
12
):
912
21
.
26.
Kim
MS
,
Fleres
B
,
Lovett
J
,
Anfinson
M
,
Samudrala
SSK
,
Kelly
LJ
, et al
.
Contractility of induced pluripotent stem cell-cardiomyocytes with an MYH6 head domain variant associated with hypoplastic left heart syndrome
.
Front Cell Dev Biol
.
2020
;
8
:
440
.
27.
Pena-Martinez
EG
,
Rivera-Madera
A
,
Pomales-Matos
DA
,
Sanabria-Alberto
L
,
Rosario-Cañuelas
BM
,
Rodríguez-Ríos
JM
, et al
.
Disease-associated non-coding variants alter NKX2-5 DNA-binding affinity
.
Biochim Biophys Acta Gene Regul Mech
.
2023
;
1866
(
1
):
194906
.
28.
Wu
KH
,
Xiao
QR
,
Yang
Y
,
Xu
JL
,
Zhang
F
,
Liu
CM
, et al
.
MicroRNA-34a modulates the Notch signaling pathway in mice with congenital heart disease and its role in heart development
.
J Mol Cell Cardiol
.
2018
;
114
:
300
8
.
29.
Pang
JKS
,
Phua
QH
,
Soh
BS
.
Applications of miRNAs in cardiac development, disease progression and regeneration
.
Stem Cell Res Ther
.
2019
;
10
(
1
):
336
.
30.
Zhang
X
,
Gao
Y
,
Zhang
X
,
Zhang
X
,
Xiang
Y
,
Fu
Q
, et al
.
FGD5-AS1 is a hub lncRNA ceRNA in hearts with tetralogy of Fallot which regulates congenital heart disease genes transcriptionally and epigenetically
.
Front Cell Dev Biol
.
2021
;
9
:
630634
.
31.
Hirano
E
,
Knutsen
RH
,
Sugitani
H
,
Ciliberto
CH
,
Mecham
RP
.
Functional rescue of elastin insufficiency in mice by the human elastin gene: implications for mouse models of human disease
.
Circ Res
.
2007
;
101
(
5
):
523
31
.
32.
He
L
,
Zhang
Q
,
Jiang
D
,
Zhang
Y
,
Wei
Y
,
Yang
Y
, et al
.
Zebrafish Foxc1a controls ventricular chamber maturation by directly regulating wwtr1 and nkx2.5 expression
.
J Genet Genomics
.
2022
;
49
(
6
):
559
68
.
33.
Jerome
L
,
Papaioannou
V
.
DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1
.
Nat Genet
.
2001
;
27
(
3
):
286
91
.
34.
Piotrowski
T
,
Ahn
DG
,
Schilling
TF
,
Nair
S
,
Ruvinsky
I
,
Geisler
R
, et al
.
The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans
.
Development
.
2003
;
130
(
20
):
5043
52
.
35.
Moore-Morris
T
,
van Vliet
PP
,
Andelfinger
G
,
Puceat
M
.
Role of epigenetics in cardiac development and congenital diseases
.
Physiol Rev
.
2018
;
98
(
4
):
2453
75
.
36.
Engwerda
A
,
Abbott
KM
,
Hitzert
MM
,
van Ravenswaaij-Arts
CMA
,
Kerstjens-Frederikse
WS
.
The role of TBX18 in congenital heart defects in humans not confirmed
.
Eur J Hum Genet
.
2023
;
31
(
2
):
138
41
.
37.
Seok
H
,
Deng
R
,
Cowan
DB
,
Wang
DZ
.
Application of CRISPR-Cas9 gene editing for congenital heart disease
.
Clin Exp Pediatr
.
2021
;
64
(
6
):
269
79
.
38.
Tyser
RCV
.
Formation of the heart: defining cardiomyocyte progenitors at single-cell resolution
.
Curr Cardiol Rep
.
2023
;
25
(
6
):
495
503
.
39.
De Zoysa
P
,
Liu
J
,
Toubat
O
,
Choi
J
,
Moon
A
,
Gill
PS
, et al
.
Delta-like ligand 4-mediated Notch signaling controls proliferation of second heart field progenitor cells by regulating Fgf8 expression
.
Development
.
2020
;
147
(
17
):
dev185249
.
40.
De Bono
C
,
Thellier
C
,
Bertrand
N
,
Sturny
R
,
Jullian
E
,
Cortes
C
, et al
.
T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field
.
Hum Mol Genet
.
2018
;
27
(
21
):
3747
60
.
41.
Augiere
C
,
Megy
S
,
El Malti
R
,
Boland
A
,
El Zein
L
,
Verrier
B
, et al
.
A novel alpha cardiac actin (ACTC1) mutation mapping to a domain in close contact with myosin heavy chain leads to a variety of congenital heart defects, arrhythmia and possibly midline defects
.
PLoS One
.
2015
;
10
(
6
):
e0127903
.
42.
Boskovski
MT
,
Homsy
J
,
Nathan
M
,
Sleeper
LA
,
Morton
S
,
Manheimer
KB
, et al
.
De novo damaging variants, clinical phenotypes, and post-operative outcomes in congenital heart disease
.
Circ Genom Precis Med
.
2020
;
13
(
4
):
e002836
.
43.
Damen
FW
,
Gramling
DP
,
Ahlf Wheatcraft
D
,
Wilpan
RY
,
Costa
MW
,
Goergen
CJ
.
Application of 4-D ultrasound-derived regional strain and proteomics analysis in Nkx2-5-deficient male mice
.
Am J Physiol Heart Circ Physiol
.
2023
;
325
(
2
):
H293
310
.
44.
Blue
GM
,
Kirk
EP
,
Giannoulatou
E
,
Sholler
GF
,
Dunwoodie
SL
,
Harvey
RP
, et al
.
Advances in the genetics of congenital heart disease: a clinician's guide
.
J Am Coll Cardiol
.
2017
;
69
(
7
):
859
70
.
45.
Radhakrishna
U
,
Albayrak
S
,
Zafra
R
,
Baraa
A
,
Vishweswaraiah
S
,
Veerappa
AM
, et al
.
Placental epigenetics for evaluation of fetal congenital heart defects: ventricular septal defect (VSD)
.
PLoS One
.
2019
;
14
(
3
):
e0200229
.
46.
Bahado-Singh
R
,
Vishweswaraiah
S
,
Mishra
NK
,
Guda
C
,
Radhakrishna
U
.
Placental DNA methylation changes in detection of tetralogy of Fallot
.
Ultrasound Obstet Gynecol
.
2020
;
55
(
6
):
768
75
.
47.
Waugh
KA
,
Minter
R
,
Baxter
J
,
Chi
C
,
Galbraith
MD
,
Tuttle
KD
, et al
.
Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model
.
Nat Genet
.
2023
;
55
(
6
):
1034
47
.
48.
Bayne
J
,
Garry
J
,
Albert
MA
.
Brief review: racial and ethnic disparities in cardiovascular care with a focus on congenital heart disease and precision medicine
.
Curr Atheroscler Rep
.
2023
;
25
(
5
):
189
95
.
49.
Acosta
JN
,
Falcone
GJ
,
Rajpurkar
P
,
Topol
EJ
.
Multimodal biomedical AI
.
Nat Med
.
2022
;
28
(
9
):
1773
84
.
50.
Hill
MC
,
Kadow
ZA
,
Long
H
,
Morikawa
Y
,
Martin
TJ
,
Birks
EJ
, et al
.
Integrated multi-omic characterization of congenital heart disease
.
Nature
.
2022
;
608
(
7921
):
181
91
.
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