先天性心臓病の遺伝的な総括

//Background//---
 Congenital heat disease (CHD) has long been recognized as the most common. Epidemiologically, CHD prevalence is 6-13 in 1,000 newborn babies(2-6). The total cost from birth to 21 years old is from $47,500 to $73,600 for each person. Therefore, healthcare resources in each country and financial burden of the patient’s family are huge. As indicated below or Ref.(1)Fig.1, congenital heart disease has several types. Advanced surgical and medical intervention have significantly reduced mortality, which is less 10%(7). However, approximately 13% of neonates with congenital heart disease has comorbidity, such as cardiovascular diseases. Stroke, depressive symptoms, neurodevelopmental delay, rheumatologic disease and asthma. The neurodevelopmental delay of children with congenital heart disease is from 8% to 22%(75,76) Adults with the congenital heart disease have higher cancer prevalence (1.4~2-fold) than general persons(77-79). Therefore, longitudinal and systemic care is needed for the patients with congenital heart diseases including comorbidity.
 Genetical identification is important for understanding of congenital heart disease pathogenesis. Approximately 12% of patients with congenital heart disease have abnormal chromosome such as trisomy 13, 18 or 21 (Down syndrome) and monosomy X (Turner syndrome)(8).
 Genes linked to the congenital heart disease provides new insight into crucial molecules and pathway involved cardiogenesis associated with dysplasia of heart. Therefore, the genetical approach by contemporary whole-exome sequencing (WEG) and whole-genome sequencing (WGS) is demanded, by which deleterious missense / loss-of-function variant / copy number variants / structural variants could be identified.
Why is CHD the most common congenital anomaly?
 Sarah U. Morton, Daniel Quiat, Jonathan G. Seidman & Christine E. Seidman consider that complex development of heart formation is exquisitely sensitive to change in (many essential) gene dosage. Therefore, they review about genemic frontiers in this decade against congenital heart disease(1). I hope to share a small part of these contents in the specific perspective with the global important readers.
I hypothesis that above reasons is due to highly heterogeneous and topological, irregular shape, asymmetric shape of the heart. For example, kidney and lung are composed of collective glomerulus and alveolus. Therefore, in the development stage, regular process exists due to similarity of each glomerulus and alveolus. On the other hand, we need to make complex connection precisely in heart development(See Fig.2). Therefore, spatiotemporal information like morphogen is important. Hence, if key mutations are emerged in the initial developmental stage, dysplasia may frequently occur than the other organs.
 
//Types of congenital heart disease//---
Ref.(1)(See Fig.1):
Epidemiological data from the Paediatric Cardiac Genomics Consortium (9,10).
(Septal defect)
Epidemiologically, 53%.
*Atrial septal defect is that blood flows between the atria (upper chambers) of the heart due to septal (a part of) loss. A part of vein route, which is mainly in right ventricle and pulmonary artery, mixed with oxygenated blood (from atrial blood).
-
*Ventricular septal defect is (a part of) loss in the ventricular septum. The extent of opening the ventricular septum may vary from pin size to complete absence. A part of vein route, which is mainly in right ventricle and pulmonary artery, is mixed with oxygenated blood (from atrial blood).
---
(Atrioventricular canal defects)
Epidemiologically, 13%
Complete atrioventricular canal defect is defect of atrial septal defect, common atrioventricular valve, common atrioventricular valve and ventricular septal defect. A part of vein route, which is mainly in right ventricle and pulmonary artery, is mixed with oxygenated blood (from atrial blood).
---
(LVOTO)
Epidemiologically, 25%
*Hypoplastic left heart syndrome is hypoplastic aorta (thin dysplasia), atrial septal defect, vessel connecting aorta and pulmonary artery, hypoplastic mitral valve and hypoplastic left ventricle(smaller space). Both atrial and vein routes, which are mainly in aorta, right atrium, right ventricle and pulmonary artery.
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(Conotruncal malformations)
Epidemiologically, 36%
*Tetralogy of Fallot is right ventricular overflow tract obstruction (narrowing), right ventricular hypertrophy, aorta overrides the ventricular septal defect, and ventricular septal defect. The mixed blood flow is mainly in aorta and near ventricular septal defect regions.
-
* D-looped transposition of the great arteries includes atrial septal defect, aorta aligned with right ventricle (dys-connection), vessel connecting aorta and pulmonary artery which is partly connected to pulmonary artery, pulmonary artery aligned with left ventricle (dys-connection). The mixed blood flow is mainly in aorta, pulmonary artery and right ventricle.
 
//Cardiac development(1)//---
*From (the fast weeks of embryogenesis) to (8 weeks of gestation for fully formation) through cardiac progenitor fields (See Fig.2 Day 15).
-
*Three major progenitor cell populations for cardiac development(11-14).
1: The first heart field (FHF), derived from the lateral plate mesoderm,
 Signalling pathways including bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) from the adjacent endoderm(15-18).
2: The second heart field (SHF), derived from the lateral plate splanchnic mesoderm.
 This field contribute progressively to the poles of the elongating heat tube during looping morphogenesis (See Fig.2 Day 21-28)
3: Migratory cardiac neural crest populating the III, IV and VI pharyngeal arches
 Cardiac neural crest cells migrate to populate the III, IV and VI pharyngeal arches, the aortic sac (AS) and the conotruncal (CT) ridges (See Fig.2 Day 28-50).
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(Genetic regulator for cardiac morphogenesis)
-
*Sarcomere formation and contraction(19-25)
GATA4, GATA6, NKX2-5, TBX5
-
*Specification of each ventricular cardiomyocytes
Left (IRX4 40, HAND1 (27) and MSX1 (28) )
Right (IRX4 (26) and GATA6 (29) )
Outflow tract (GATA6 (29), HAND2 (27) , ARID3B(30) and TEAD(31)).
-
*Cardiac neural crest migration
FOXC2(32)
-
*Non-chamber myocardium
TBX2, TBX3(33), BMP2, BMP4(34)
-
*Left-right signalling axis
Nodal, Lefty1, Lefty2 and Zic3 (35-37): TGF-beta family members
 
//Human cardiac dysplasia//---
(Conotruncal defects)
Conotruncal defects is following(#).
(#)Tetralogy of Fallot / Persistent truncus arteriosus / Transposition of the great arteries / Reflect maldevelopment of the ventricular septum in the outflow tract / the great arteries / malalignment of these structures.
-
*Deletion of genes
TBX1(38), CHD7(39), GJA5 and CHD1L(40,41)
-
*Monogenic LOF variants
The Notch pathway (NOTCH1)
The VEGF pathway (KDR, FLT4, VEGFA, FGD5, BCAR1, IQGAP1, FOXO1 and PRDM1) (42,43)
Signaling pathways orchestrating developmental program.
-
*Autosomal dominant damaging variants
ZFPM2, GATA4 and GATA6(44-46)
---
(Atrial and ventricular septal defects)
*Ventricular septation defect is derived from abnormality of heart tissue elongation stage (SHF), which is the dorsam mesenchymal protrusion(71,72).
*Damaging variants in NKX2-5 and GATA4
TBX5 variants                    
---
(Left-sided obstructive lesions)
 Left-sided obstructive type includes the spectrum of stenotic and atretic anomalies of the left­side chambers and valves(#)(1).
(#)Isolation (mitral stenosis, bicommissural aortic valve, aortic stenosis and coarctation of the aorta) or in combination, such as Shone complex (annulo­leaflet mitral ring, parachute mitral valve, subaortic stenosis and coarctation of the aorta) and hypoplastic left heart syndrome (mitral and aortic stenosis or atresia, and hypoplastic left ventricle)(1).
-
*Patients with monosomy X or Turner syndrome (45,XO karyotype)
Bicommissural aortic valve (15–30%), aortic coarctation (7–20%)(47,48)
-
*Patient with autosomal dominant Jacobsen syndrome (11q23 deletion)
Diverse and severe left-sided obstructive lesions in 33%(49).
-
*Monogenic damaging variants in GATA5
Bicuspid aortic valve(50,51).
-
* Monogenic damaging variants RBFOX2
Hypoplastic left heart syndrome(52).
---
(Right-sided obstructive lesions)
 Blood flow obstruction from the right side of the heart to the pulmonary capillary beds can occur in tricuspid atresia / pulmonary atresia with intact ventricular septum / isolated pulmonary valve stenosis supravalvular / branch pulmonary artery stenosis.
-
*Pulmonary valve stenosis is present in >50% of children with Noonan syndrome.
Associated gene: PTPN11(53)
-
*Autosomal dominant and recessive forms of Robinow syndrome
Pathogenic variants: WNT5A, ROR2, DVL1 and DVL3)(54-57)
-
*Autosomal dominant Alagille syndrome
Associated gene: JAG1 and NOTCH2
---
(Left-right patterning defects)
 Defects in left-right axis patterning cause heterotaxy syndrome, resulting in abnormal positioning of the viscera as well as congenital heart diseases that includes structural malformations and aberrant arterial and venous connections. Normal cilia function is crucial for left-right axis patterning,
* Damaging variants in Nodal and TGFβ signalling pathway genes
(NODAL, FOXH1, ZIC3, ACVR2B and SMAD2)(58,59)
-
* X-linked heterotaxy syndrome in hemizygous males
Associated gene: ZIC3(60,61)
 
//Definitive genes of CHD from cohort studies//---
*Following 18 genes(#) were significantly enriched in these two WES cohorts(62-64)
(#)ADNP, ANKRD11, CDK13, CHD4, CHD7, DDX3X, DYRK1A, FLT4, KMT2A, KMT2D, NOTCH1, NSD1, PACS1, PRKD1, PTPN11, RBFOX2, SMAD6 and TAB2
-
CHD7 (CHARGE syndrome), KMT2D (Kabuki syndrome), NSD1 (Sotos syndrome) and PTPN11 (Noonan syndrome),
-
*Syndromic congenital heart disease
Associated gene: CDK13, CHD4 and PRKD1 (variant)(73)
*(histologic) Isolated congenital heart disease
Associated gene: SMAD6 (variant)(74)
 
//Induced pluripotent stem cell models//---
 Human cell derived induced pluripotent stem cell (hiPS cell) enables the trace of early heart development model and arbitrary pathway-based study against key mutations.
---
(Early development model)
1: The first heart field (FHF), derived from the lateral plate mesoderm,
2: The second heart field (SHF), derived from the lateral plate splanchnic mesoderm,
3: Migratory cardiac neural crest populating the III, IV and VI pharyngeal arches
These early development models are confirmed(65-69).
---
(Pathway-based study/ For example.)
hiPSCs with GATA6 LOF variants show disruption of crucial downstream regulators associated
with outflow tract development (KDR and HAND2), which proves association of GATA6 LOF variants and outflow tract malformations in human cell(70).
 
//Contribution of genome analysis//---
 Understanding of association between related gene and clinical statement contribute to improve the precise diagnosis and classification, by which the physician enables proper clinical care of patients with congenital heart diseases.
 It may be difficult to medically (genetically) intervene this disease before early heart development also from an ethical perspective, but detailed genetic analysis holds great opportunities to understand the development biology in heart. This can contribute to provide the heart transplantation and regeneration medicine (through induced pluripotent stem cell technology.)
 
//Contributions(Ref.(1))//---
All the authors contributed to researching data for the article, discussion of content, writing the article, and reviewing and editing the manuscript before submission.
 
//Ethics declarations(Ref.(1))//---
Competing interests
The authors declare no competing interests.
 
//Peer review information(Ref.(1))//---
Nature Reviews Cardiology thanks V. Garg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
 
//Publisher’s note(Ref.(1))//---
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
 
(Reference)
(1)
Sarah U. Morton, Daniel Quiat, Jonathan G. Seidman & Christine E. Seidman
Genomic frontiers in congenital heart disease
Nature Reviews Cardiology (2021)
---
Author information
Author notes
These authors contributed equally: Sarah U. Morton, Daniel Quiat.
Affiliations
Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Boston, MA, USA
Sarah U. Morton
Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Sarah U. Morton & Daniel Quiat
Department of Genetics, Harvard Medical School, Boston, MA, USA
Sarah U. Morton, Daniel Quiat, Jonathan G. Seidman & Christine E. Seidman
Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
Daniel Quiat
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
Christine E. Seidman
Howard Hughes Medical Institute, Harvard University, Boston, MA, USA
Christine E. Seidman
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