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"I find it so amazing that we know so little
about the most common type of birth defect
in both Australia and around the world.
Every child deserves the right to a healthy
start to life, but sadly this is
not always the case,"

- Professor Sally Dunwoodie 


Professor Sally Dunwoodie

Head, Embryology Laboratory

research overview

Key Research Areas 

  • Embryonic development
  • Congenital heart disease
  • Genetic and environmental causes of birth defects

Research Overview 

Congenital malformation occurs in 3-6% of births and in 80% of cases the cause is unknown. The heart is the first organ to form and function during the development of an embryo. When it does not form properly the baby is born with a heart defect, collectively described as congenital heart disease (CHD). CHD is the most common type of birth defect.  In Australia, 42 babies are born with a heart defect every week.

 The Embryology Laboratory is identifying the genetic and environmental causes of birth defects, including CHD. Gene mutations are being identified in patients. Mouse models are being developed to understand how genetic mutations and environmental factors impact on embryogenesis. 

research projects

There are 4 key projects underway in the Embryology Laboratory, led by Professor Sally Dunwoodie;

1. Genetic causes of congenital malformation

Families with congenital malformation are being recruited and gene mutations are being identified using whole genome sequencing, and in house bioinformatics. Some mutations occur in genes known to cause congenital malformation. These mutations are tested for pathogenicity using an array of in vitro assays. Many mutations arise in “new” genes and thus their relevance to congenital malformation is being established in preclinical models, such as the mouse.
We have discovered that:

  • mutations in DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 cause vertebral defects
  • mutations in genes KYNU or HAAO result in nicotinamide adenine dinucleotide (NAD) deficiency causing multiple congenital malformations in affected individuals

2. Environmental causes of congenital malformation

We are determining if risk factors associated with congenital malformation in humans, disrupt embryogenesis in mice. Moreover, a number of risk factors lead to hypoxia in the embryo; therefore, we use short-term gestational hypoxia to disrupt embryogenesis and determine the molecular and cellular sequelae.
We have discovered that:

  • hypoxia inhibits fibroblast growth factor (FGF) signalling, which disrupts heart and vertebral formation
  • hypoxia induces the unfolded protein response (UPR) and in doing so inhibits FGF signalling

3. Gene-Environment interaction (GxE) as a cause of congenital malformation

A genetic predisposition to a birth defect might, in combination with an adverse environmental stress, disrupt embryogenesis. In mouse, we are exploring the extent to which GxE disrupts embryogenesis.
We have discovered that:

  • GxE causes vertebral and kidney defects in mice

4. Nicotinamide adenine dinucleotide (NAD) deficiency and congenital malformation

In families, we discovered that NAD deficiency causes multiple congenital malformations in affected individuals. In mice, NAD deficiency was prevented and embryo defects averted by dietary supplementation with niacin/vitamin B3. Read more here.

Laboratory members & collaborators

Laboratory

Dr Gavin Chapman, Senior Staff Scientist  

Dr Julie Moreau, Postdoctoral Scientist 

Dr Hartmut Cuny, Postdoctoral Scientist 

Dr Dimuthu Alankarage, Postdoctoral Scientist 

Dr Justin Szot, Postdoctoral Scientist

Dr Annabelle Enriquez, Clinical Geneticist, PhD Student 

Ella Martin, Research Assistant 

Melissa Rapada, Research Assistant  

Kavitha Iyer, Research Assistant 

Joelene Major,Research Assistant 

Victoria O’Reilly, Research Assistant 

Jessica Gereis, BSc Honours Student 

Rosemary Kirk, Medical Honours Student 

Collaborators 

Dr Alison Colley, Sydney South West Area Health Service, Australia 

Dr Felicity Collins, Children’s Hospital at Westmead, Australia 

Professor Emma Duncan, Queensland University of Technology, Australia 

Professor Philip Giampietro, Drexel University College of Medicine, USA

Dr Encarna Guillen Navarro, Hospital Universitario Virgen de la Arrixaca, Spain

Dr Haifa Hong, Shanghai Children's Medical Center, China

Professor Edwin Kirk, Sydney Children's Hospital, Australia

Professor Kenro Kusumi, Arizona State University, USA

Dr Paul Mark, Spectrum Health, Grand Rapids, USA

Dr Leslie McGregor, South Australian Clinical Genetics Service, Australia

A. Professor Nicholas Pachter, Genetic Services of Western Australia, Australia

Dr Helen Ritchie, University of Sydney, Australia

Dr Fatma Silan, Canakkale Onsekiz Mart University, Turkey

Professor David Sillence, Children’s Hospital at Westmead, Australia

Dr Hongjun Shi, Westlake Institute for Advanced Study, Hangzhou, China 

Dr Janine Smith, Children’s Hospital at Westmead, Australia

Dr Roger Stevenson, Greenwood Genetic Center, South Carolina, USA

Dr Hui Sun, Mount Sinai School of Medicine, USA

Dr Elizabeth Thompson, Women’s & Children’s Hospital, Australia

Professor Peter Turnpenny, Royal Devon & Exeter Hospital, UK

Dr Sue White, Genetic Health Services Victoria, Australia

Professor David Winlaw, Children’s Hospital at Westmead, Australia

Dr Nan Wu, Peking Union Medical College Hospital, China

publication highlights

1. Shi H, Enriquez A, Rapadas M, Martin EMMA. Wang R, Moreau J, Lim CK, Szot JO, Ip E, Hughes J, Sugimoto K, Humphreys D, McInerney-Leo AM, Leo PJ, Maghzal GJ, Halliday J, Smith J, Colley A, Mark PR, Collins F, Sillence DO, Winlaw DS, Ho J, Guillemin GJ, Brown MA, Kikuchi K, Thomas PQ, Stocker R, Giannoulatou E, Chapman G, Duncan EL, Sparrow DB, Dunwoodie SL. NAD Deficiency, Congenital Malformations and Niacin Supplementation. The New England Journal of Medicine. 2017; 377(6):544-552.

2.  Blue GM, Kirk EP, Giannoulatou E, Sholler GF, Dunwoodie SL, Harvey RP, Winlaw DS. Advances in the genetics of congenital heart disease: A Clinician’s guide. Journal of the American College of Cardiology. 2017; 69(7):859-870.

3. Shi H, O’Reilly VC, Moreau JLM, Bewes TR, Yam MX, Chapman BE, Grieve SM, Stocker R, Graham RM, Chapman G, Sparrow DB and Dunwoodie SL. Gestational Stress Induces the Unfolded Protein Response Resulting in Heart Defects. Development. 2016; 143(14):2561-2572.

4. Wu N,  Ming X, Xiao J, Wu Z, Chen X, Shinawi M, Shen Y, Yu G, Liu J, Xie H,  Gucev ZS, Liu S, Yang N, Al-Kateb H, Chen J, Zhang J, Hauser N, Zhang T, Tasic V, Liu P, Su X, Pan X, Liu C,  Wang L, Shen J, Shen J, Chen Y, Zhang T, Zhang J, Choy KW,  Wang J,  Wang Q, Li S,  Zhou W, Guo J, Wang Y, Zhang C, Zhao H, An Y, Zhao Y, Wang J, Liu Z, Zuo Y, Tian Y, Weng X, Sutton VR, Wang H, Ming Y, Kulkarni S, Zhong TP, Giampietro PF, Dunwoodie SL, Cheung SW, Zhang X, Jin L, Lupski JR, Qiu G, Zhang F. TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis. New England Journal of Medicine. 2015; 372(4):341-50 

5. McInerney-Leo AM, Sparrow DB, Harris JE, Gardiner BB, Marshall MS, O'Reilly VC, Shi H, Brown MA, Leo PJ, Zankl A*, Dunwoodie SL*, Duncan EL*. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Human Molecular Genetics. 2015; 24(5):1234-42 *equal contribution. 

6. Blue GM, Kirk EP, Giannoulatou E, Dunwoodie SL, Ho JWK, Hilton DCK, White SM, Sholler GF, Harvey RP, Winlaw DS. Targeted next generation sequencing identifies pathogenic variants in familial CHD. Journal of the American College of Cardiology. 2014; 64(23):2498-506.

7. O'Reilly VC, Lopes Floro K, Shi H, Chapman BE, Preis JI, James AC, Chapman G, Harvey RP, Johnson RS, Grieve SM, Sparrow DB and Dunwoodie SL. Gene-environment interaction demonstrates the vulnerability of the embryonic heart. Developmental Biology. 2014; 391(1):99-110. 

8. Sparrow DB, McInerney-Leo A, Gucev ZS, Gardiner B, Marshall M, Leo PJ, Chapman DL, Tasic V, Shishko A, Brown MA, Duncan EL, Dunwoodie SL. Autosomal Dominant Spondylocostal Dysostosis is Caused by Mutation in TBX6. Human Molecular Genetics. 2013; 15;22(8):1625-31.

9. Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O’Reilly VC, Saga Y, Zackai EH, Dormans DP, Alman BA, McGregorL, Kageyama R, Kusumi K, Dunwoodie SL. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012; 149(2):295-306. 

10. Chapman G, Sparrow DB, Kremmer E and Dunwoodie SL. Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Human Molecular Genetics. 2011; 20(5):905-16.

11. Dunwoodie SL. The role of hypoxia in development of the mammalian embryo. Developmental Cell. 2009; 17(6):755-773.

12. Sparrow DB, Boyle SC, Sams RS, Mazuruk B, Zhang L, Moeckel GW, Dunwoodie SL, de Caestecker MP. Placental insufficiency causes renal medullary dysplasia in Cited1 mutant mice. Journal of The American Society of Nephrology. 2009; 20(4): 777-86

13. Sparrow D, Guillen-Navarro E, Fatkin D, Dunwoodie SL. Mutation of HAIRY-AND-ENHANCER-OF-SPLIT-7 in Humans Causes Spondylocostal Dysostosis. Human Molecular Genetics. 2008; 17(23):3761-6.

14. Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. American Journal of Human Genetics. 2006; 78(1):28-37.

15. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard D, Dunwoodie SL, Peter D. Turnpenny. Mutated MESP2 causes spondylocostal dysostosis in humans. American Journal Human Genetics. 2004; 74(6):1249-54.

16. Turnpenny PD, Whittock N, Duncan J, Dunwoodie SL, Kusumi K, Ellard S. Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. Journal of Medical Genetics. 2003; 40:333-39.

17. Martinez Barbera JP, Rodriguez TA, Greene N, Weniger WJ, Simeone A, Copp A, Beddington RSP, Dunwoodie SL. Administration of folic acid prevents exencephaly in Cited2 deficient mice. Human Molecular Genetics. 2002; 11(3):283-93.

18. Dunwoodie SL*, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RSP. Axial skeletal defects caused by mutation in the spondylocostal dysostosis/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development. 2002; 129:1795-806. (*Corresponding author).

19. Avner P, Bruls T, Poras I, Eley L, Gas S, Ruiz P, Wiles MV, Sousa-Nunes R, Kettleborough R, Rana A, Morrisette J, Bentley L, Goldsworthy M, Haynes A, Herbert E, Southam L, Taghavi V, Sartory E, Lehrach H, Weissenbach J, Manenti G, Rodriguez-Tome P, Beddington RSP, Dunwoodie SL, Cox R. A radiation hybrid transcript map of the mouse genome. Nature Genetics. 2001; 29(2):194-200.

20. Harrison SM, Dunwoodie SL., Arkell RM, Lehrach H, Beddington RSP. Isolation of novel tissue-specific genes from cDNA libraries representing the individual tissue constituents of the gastrulating mouse embryo. Development. 1995; 121:2479-489.

To read more of Professor Sally Dunwoodie's work, please click here and here.

list of congenital heart disease genes

This is a list of genes, known to reproducibly cause human congenital heart disease (CHD) when mutated (human curated - high confidence CHD list). It has utility for clinicians and geneticists for prioritising variants found in exome or genome sequences. Details about the curation process and inclusion criteria for genes have been published and can be found here.

This gene list will continue to be updated to account for the growing number of published data about human gene-disease-relationships.

For enquiries regarding the gene list, please email chdgenes@victorchang.edu.au.

Gene1

Human CHD phenotype2

Syndrome with associated CHD3

Animal models4

Ref.5

ACTC1

ASD, VSD

Homozygous null mouse has CHD

1, 2, 3

ACVR1

ASD, AVSD, DORV, TGA

Mouse with endothelial-specific conditional deletion has CHD

4, 5

ACVR2B

ASD, AVSD, CAVC, DORV, MA, PA, PS, TAPVR, TGA, VSD, right-sided aortic arch, common atrium

Heterotaxy

Homozygous null mouse has CHD

6, 7

BMPR2

ASD, PAPVR, PDA, TGA, VSD, atrioventricular canal

Mice with homozygous single-base mutation or homozygous deletion of exon 2 have CHD

8, 9

BRAF

ASD, BAV, PS, mitral valve anomaly

Cardiofaciocutaneous syndrome (115150, AD), LEOPARD syndrome 3 (613707, AD), Noonan syndrome 7 (613706, AD)

Homozygous null mouse has CHD

10, 11, 12, 13

CDK13

ASD, VSD, outflow tract defects

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (617360, AD)

no cardiovascular defects reported

14, 15

CFC1

AVSD, DORV, IAA, TGA, TOF, tricuspid atresia,

Heterotaxy

Mice with homozygous single-base mutations or homozygous null allele have CHD

16, 17, 18, 19

CHD4

ASD, CoA, TOF, VSD

Sifrim-Hitz-Weiss syndrome (617159, AD)

no cardiovascular defects reported

15

CHD7

ASD, aberrant supraclavicular artery

CHARGE syndrome (214800, AD)

Mice with heterozygous stopgain mutation or heterozygous null allele have CHD

20, 21, 22

CITED2

ASD, VSD

Heterozygous and homozygous null mice have CHD

23, 24, 25

CREBBP

ASD, BAV, CoA, PDA, PS, VSD

Rubinstein-Taybi syndrome (180849, AD)

Heterozygous null mouse has CHD

26, 27, 28, 29, 30

CRELD1

AVSD, dextrocardia

no cardiovascular defects reported

31, 32

EFTUD2

ASD, PDA, VSD

Mandibulofacial dysostosis, Guion-Almeida type (610536, AD)

no cardiovascular defects reported

33, 34

EHMT1

VSD, asymmetric aortic valve

Kleefstra syndrome (610253, AD)

Mouse with cardiomyocyte-specific conditional knockout has CHD

35, 36

ELN

ASD, supravalvular aortic stenosis

Heterozygous and homozygous null mice have CHD

37, 38

EVC

ASD, PS, TGA, VSD, common atrium, atrioventricular canal defect

Ellis-van Creveld syndrome  (225500, AR), Weyers acrodental dysostosis  (193530, AD)

no cardiovascular defects reported

39, 40, 41, 42

EVC2

ASD, PS, TGA, VSD, common atrium, atrioventricular canal defect

Ellis-van Creveld syndrome  (225500, AR), Weyers acrodental dysostosis  (193530, AD)

no cardiovascular defects reported

39, 40, 41, 42

FBN1

AS, MVP, Mitral insufficiency, tricuspid stenosis, aortic valve insufficiency

Marfan syndrome (154700, AD)

Heterozygous and homozygous null mice have CHD

43, 44

FLNA

ASD, CoA, DORV, HLV, MA, PDA, valve insufficiency, mono-atrium

Female mice heterozygous and male mice hemizygous for a single-base mutation or null allele have CHD

45, 46, 47

FOXC1

ASD, TOF

Axenfeld-Rieger syndrome, type 3 (602482, AD)

Heterozygous and homozygous null mice have CHD

48, 49, 50

FOXC2

PDA, TOF, VSD

Lymphedema-distichiasis syndrome (with or without renal disease and diabetes mellitus) (153400, AD)

Homozygous null mouse has CHD

51, 52

FOXH1

TGA, TOF

Mice homozygous for a single point mutation or null allele have CHD

19, 53

GATA4

ASD, AVSD, PAPVR, PS, TOF, VSD

Homozygous null mouse has CHD, mice homozygous or heterozygous for single-base mutations have CHD

54, 55, 56, 57

GATA5

ASD, BAV, TOF, VSD

Homozygous null mouse has CHD

58, 59, 60

GATA6

ASD, PDA, PS, PTA, TOF

Mouse with conditional deletion has CHD

61, 62, 63, 64

GDF1

DORV, MAPCAs, PA, PS, TGA, TOF, dextrocardia, common atrium,

Heterotaxy

Homozygous null mouse has CHD

65, 66

GJA1

HLHS, PA, VSD, right ventricular hypoplasia, tricuspid stenosis

Oculodentodigital dysplasia (164200, AD), heterotaxy

Homozygous null mouse has CHD

67, 68

GPC3

ASD, PDA, PFO, VSD, tricuspid valve hypoplasia, thickened pulmonary valve, hypoplastic left pulmonary artery

Simpson-Golabi-Behmel syndrome, type 1 (312870, XLR)

Male mice with hemizygous deletion have CHD

69, 70, 71

HAND1

hypoplastic ventricle, VSD

Heterozygous and homozygous null mice have CHD

 

72, 73, 74

HAND2

PS, TOF, VSD

Homozygous null mouse has CHD

75, 76

HRAS

ASD, BAV, MVS, PS

Costello syndrome (218040, AD)

Mouse with homozygous single-base mutation has CHD

13, 77, 78

INVS

PFO, PVS, VSD, mitral insufficiency

Nephronophthisis 2, infantile (602088, AR)

Homozygous null mouse has CHD

79, 80

JAG1

PS, TOF, VSD, aortic dextroposition

Alagille syndrome 1 (118450, AD)

Mouse with conditional endothelial-specific deletion has CHD

81, 82

KANSL1

ASD, BAV, PFO, PS, VSD, mitral insufficiency, anomalous right subclavian artery

Koolen-De Vries syndrome (610443, AD)

no cardiovascular defects reported

83, 84

KAT6A

ASD, MVP, PDA, PFO, VSD

Mental retardation, autosomal dominant 32 (616268, AD)

Heterozygous and homozygous null mice have CHD

85, 86, 87

KAT6B

ASD, PDA, PFO, VSD

Genitopatellar syndrome (606170, AD), SBBYSS syndrome (603736)

no cardiovascular defects reported

88, 89, 90, 91

KDM6A

ASD, PS, VSD, hypoplastic right ventricle

Kabuki syndrome 2 (300867, XLD)

Homozygous null and male mice with hemizygous deletion have CHD

92, 93, 94

KMT2D

ASD, BAV, CoA, VSD

Kabuki syndrome 1 (147920, AD)

Mice with conditional deletion in different cell types have CHD

95, 96, 97, 98

KRAS

ASD, PS, VSD, tricuspid valve prolapse, cleft mitral valve, dysplastic mitral valve

Noonan syndrome 3 (609942), Cardiofaciocutaneous syndrome 2 (615278)

Mice homozygous for single-base mutation or null allele have CHD

11, 99, 100

MAP2K1

ASD, PS

Cardiofaciocutaneous syndrome 3 (615279)

Homozygous null mouse has vascular defects but no CHD

12, 101, 102

MAP2K2

ASD, BAV, PS, PVS, pulmonary valve dysplasia

Cardiofaciocutaneous syndrome 4 (615280)

no cardiovascular defects reported

12, 101, 102

MED13L

PFO, TGA, TOF, VSD

Mental retardation and distinctive facial features with or without cardiac defects (616789, AD)

no cardiovascular defects reported

103, 104, 105, 106

MYBPC3

ASD, PDA, PFO, VSD, mitral valve regurgitation

Homozygous null mouse has CHD

107, 108

MYH6

AS, ASD, PFO, TGA, VSD, tricuspid atresia

Mice heterozygous or homozygous for a null allele or single-base mutation have CHD

109, 110

MYH7

ASD, Ebstein anomaly, left ventricular noncompaction

no cardiovascular defects reported

111, 112, 113

MYH11

PDA, aortic aneurysm

Homozygous null mouse has CHD

 

114, 115

NF1

ASD, CoA, PS, PVS, VSD, mitral valve thickening,

Neurofibromatosis-Noonan syndrome (601321, AD)

Homozygous null mouse has CHD

116, 117, 118

NIPBL

ASD, MVP, VSD

Cornelia de Lange syndrome 1 (122470, AD)

Heterozygous null mouse has CHD, morpholino knockdown in zebrafish leads to CHD

119, 120, 121, 122

NKX2-5

ASD, AVSD, CoA, DORV, HLHS, IAA, TGA, TOF, VSD, Ebstein anomaly

Heterotaxy

Heterozygous and homozygous null mice have CHD, mouse homozygous for a single-base mutation has CHD

123, 124

NKX2-6

DORV, PTA, TOF, VSD, complex conotruncal defect

no cardiovascular defects reported

125, 126, 127

NODAL

ASD, AVSD, CoA, DORV, PA, PAPVR, PDA, TAPVR, TGA, VSD, double-inlet left ventricle, single ventricle, single atrium

Heterotaxy

Heterozygous and homozygous null mice have CHD

128

NOTCH1

AS, BAV, CoA, HLHS, LVOTO, TOF

Heterozygous and homozygous null mice have CHD

129, 130

NOTCH2

ASD, PDA, PS, TOF

Alagille syndrome 2 (610205, AD), Hajdu-Cheney syndrome, 102500, AD)

Mouse homozygous for a hypomorphic allele has CHD

131, 132, 133

NPHP3

AS, ASD, PDA, dysplasia of valve cusps, mitral insufficiency

Meckel syndrome 7 (267010), Nephronophthisis 3 (604387), Renal-hepatic-pancreatic dysplasia 1 (208540)

Homozygous null mouse has CHD

80, 134

NPHP4

AVSD, DORV, TGA, dextrocardia

Heterotaxy

Mouse with homozygous stopgain mutation has subtle vascular defects but no CHD

135

NR2F2

ASD, AVSD

Homozygous null mouse has CHD

136, 137

NRAS

PS, mitral valve dysplasia

Noonan syndrome 6 (613224, AD)

no cardiovascular defects reported

138, 139

NSD1

ASD, BAV, PDA, PFO, PS, VSD, Epstein anomaly

Sotos syndrome 1 (117550, AD)

no cardiovascular defects reported

140, 141

PITX2

ASD, DORV, TGA, TOF, VSD, mitral valve cleft, right-sided aortic arch

Axenfeld-Rieger syndrome, type 1 (180500, AD)

Homozygous null mouse has CHD

142, 143, 144, 145

PRDM6

PDA

Homozygous null mouse has mild CHD (thin myocardium)

146

PRKD1

AVSD, TA, pulmonary valve abnormality

Mouse with cardiac-specific conditional deletion has CHD

15, 147

PTPN11

ASD, PS, mitral valve anomaly

LEOPARD syndrome 1 (151100, AD), Noonan syndrome 1 (163950, AD)

Mice heterozygous or homozygous for a single-base mutation or homozygous for a null allele have CHD

10, 13, 148, 149

RAB23

ASD, DORV, PDA, TOF

Carpenter syndrome (201000, AR)

Homozygous null mouse has CHD and morpholino knockdown in zebrafish leads to laterality defects

150, 151, 152

RAD21

PFO, TOF

Cornelia de Lange syndrome 4 (614701, AD)

no cardiovascular defects reported

153, 154

RAF1

ASD, PFO, PS, TOF, VSD, pulmonary valve dysplasia

LEOPARD syndrome 2 (611554), Noonan syndrome 5 (611553)

Mouse heterozygous for a single-base mutation has CHD

99, 155, 156

RIT1

ASD, MVP, PDA, PS, VSD, mitral valve regurgitation

Noonan syndrome 8 (615355, AD)

No cardiovascular defects reported for mice, zebrafish injected with mutant transcripts have CHD

157, 158, 159

SALL1

ASD, TA, VSD, absent pulmonary valve

Townes-Brocks syndrome (107480, AD)

No cardiovascular defects reported

160, 161

SALL4

PDA, TOF, VSD

Duane-radial ray syndrome (607323, AD)

Heterozygous null mouse has CHD

162, 163, 164

SF3B4

AVSD, PDA, TOF

Acrofacial dysostosis 1, Nager type (154400, AD)

No cardiovascular defects reported

165, 166, 167

SHOC2

ASD, PS, VSD, mitral dysplasia, tricuspid dysplasia

Noonan-like syndrome with loose anagen hair (607721, AD)

No cardiovascular defects reported

13, 148, 168

SMAD3

HLHS, MVS, PDA, PS, VSD, aortic insufficiency,

Loeys-Dietz syndrome 3 (613795, AD)

Homozygous null mouse has subtle vascular defects but no CHD

169, 170, 171

SMAD4

AS, ASD, MVS, PDA, PS, VSD, aortic valve stenosis, juxtaductal coarctation, polyvalvar dysplasia

Myhre syndrome (139210, AD)

Mouse with myocardial-specific conditional deletion has CHD

148, 172

SMAD6

AS, BAV, CoA, mitral valve regurgitation

Homozygous null mouse has CHD

173

SMC1A

ASD, PS, VSD

Cornelia de Lange syndrome 2 (300590, XLD)

No cardiovascular defects reported

120, 174, 175

SMC3

AS, ASD, BAV, PDA, PS, TOF, VSD, pulmonary artery dysplasia and hypoplasia

Cornelia de Lange syndrome 3 (610759, AD)

No cardiovascular defects reported

120, 176

SON

ASD, PDA, VSD, aortic valve regurgitation

ZTTK syndrome (617140, AD)

No cardiovascular defects reported

177, 178, 179

SOS1

ASD, PS, VSD

Noonan syndrome 4 (610733, AD)

Mice heterozygous or homozygous for a single-base mutation or homozygous for a null allele have CHD

10, 13, 99, 148

STRA6

ASD, CoA, HLHS, HLV, PDA, TOF, VSD, pulmonary trunk and pulmonary artery absence, dilated ductus arteriosus, right-sided aortic arch, dextroposed aorta

Microphthalmia, syndromic 9 (601186, AR)

Homozygous null mice have isolated cardiovascular defects, but no CHD

180, 181, 182

TAB2

ASD, PDA, PS, TOF, VSD, aortic root dilatation, polyvalvular syndrome

Mouse with endothelial-specific conditional deletion has cardiovascular defects but no CHD

183, 184

TBX1

DORV, IAA, VSD

DiGeorge syndrome (188400, AD), Velocardiofacial syndrome (192430, AD)

Mice heterozygous or homozygous for single-base mutations or a null allele have CHD

185, 186, 187

TBX20

ASD, CoA, DORV, HLV, MVS, PDA, PFO, VSD

Mice heterozygous or homozygous for a null allele have CHD

188, 189

TBX5

ASD, AVSD, VSD

Holt-Oram syndrome (142900, AD)

Mice heterozygous or homozygous for a null allele have CHD

190, 191, 192

TFAP2B

PDA

Char syndrome (169100, AD)

Mice heterozygous or homozygous for a null allele have CHD

193, 194

TGFBR1

ASD, MVP, PDA

Loeys-Dietz syndrome 1 (609192, AD)

Homozygous null mouse has cardiovascular defects but no CHD

195, 196

TGFBR2

ASD, BAV, MVP, PDA, bicuspid pulmonary valve

Loeys-Dietz syndrome 2 (610168, AD)

Homozygous null mouse has cardiovascular defects, mouse with neural crest-specific conditional deletion has CHD

195, 196

TLL1

ASD, PDA, VSD

Mice homozygous for a single-base mutation or homozygous for a null allele have CHD

197, 198, 199

UBR1

ASD, PDA, TOF, VSD

Johanson-Blizzard syndrome (243800, AR)

No cardiovascular defects reported

200, 201, 202

ZEB2

ASD, PDA, PS, VSD

Mowat-Wilson syndrome (235730, AD)

Mouse with neural crest-specific conditional deletion has CHD

203, 204, 205

ZFPM2

DORV, TGA, TOF

Mice homozygous for a single-base mutation or homozygous for a null allele have CHD

206, 207

ZIC3

ASD, TGA, PS

Heterotaxy, VACTERL association, X-linked (314390, XLR)

Mice heterozygous or homozygous for a null allele or homozygous for a single-base mutation have CHD

208, 209, 210


2
Abbreviations of structural heart defects: AS: Aortic stenosis; ASD: Atrial septal defect; AVSD: Atrioventricular septal defect; BAV: Bicuspid aortic valve; CAVC: Complete atrioventricular canal defect; CoA: Coarctation of the aorta; DORV: Double-outlet right ventricle; HLHS: Hypoplastic left heart syndrome; HLV: Hypoplastic left ventricle: IAA: Interrupted aortic arch; LVOTO: Left ventricular outflow tract obstruction; MA: Mitral atresia; MAPCAs: Major aortopulmonary collateral arteries; MVS: Mitral valve stenosis; MVP: Mitral valve prolapse; PA: Pulmonary atresia; PAPVR: Partial anomalous pulmonary venous return; PDA: Patent ductus arteriosus; PFO: Patent foramen ovale; PS: Pulmonary stenosis; PTA: Persistent truncus arteriosus; PVS: Pulmonary valve stenosis; TA: Truncus arteriosus; TAPVR: Total anomalous pulmonary venous return; TGA: Transposition of the great arteries; TOF: Tetralogy of Fallot; VSD: Ventricular septal defect

3The numbers refer to the Phenotype MIM number in the OMIM database (https://omim.org/). AD: Autosomal dominant; AR: Autosomal recessive; XLD: X-linked dominant; XLR: X-linked recessive

4Phenotype data was collected from the Mouse Genome Informatics database (http://www.informatics.jax.org/) and complemented with data from publications in selected cases.   

5Selected references reporting human patient cases and linking the observed congenital defects to the respective gene.

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