Genetic Testing in Congenital Heart Disease

Which test for which lesion, when to refer, recurrence risk, and cardiac screening by syndrome; adult rows labelled

Which test first

Who	Test	Source
Fetus with CHD	Genetic counseling with an offer of aneuploidy testing, plus a detailed anatomy survey I A	AHA 2014
Fetus with CHD	Amniocentesis with CMA offered whatever the screening result; CMA on cord blood if declined	NSGC 2021
Any CHD	If testing, CMA is the first-tier test to consider	NSGC 2021
22q11.2 lesions	22q11.2 deletion by CMA in every patient with IAA, truncus, TOF, VSD* with an arch anomaly, isolated arch anomaly, or CHD with another 22q11.2DS feature	AHA 2018 Table 3, text
Aneuploidy suspected	Karyotype and/or FISH for suspected trisomy 13, 18, 21 or Turner, or to look for a translocation	NSGC 2021
One syndrome suspected	Consider gene or panel testing, ideally with a geneticist, e.g. RASopathy or heterotaxy panel, ELN, JAG1, TBX5, CHD7	NSGC 2021
Anomaly before 1 y	Exome or genome sequencing as a first- or second-tier test, strong recommendation	ACMG 2021
Adult	Conotruncal defect: screening for 22q11.2 deletion syndrome is reasonable 2a B-NR	ACHD 2025

What each test detects (AHA 2018 Table 1)

Sensitivity: – not detected, + low, ++ medium, +++ high
Test	Genomic vs Targeted	Aneuploidies and Chromosomal Rearrangements	Copy Number Variation	SNPs and INDELS	Example of Clinical Use
Karyotype	Genomic	+++	+	–	Confirmation of trisomy 21
Array CGH	Genomic	++	+++	–	Multiple congenital anomalies without obvious syndromic association
FISH	Targeted	+	+	–	Suspected 22q11.2 deletion syndrome
Gene panel testing	Targeted	–	+	+++	Suspected monogenic disease with a small differential diagnosis
Exome sequencing	Genomic	–	–	+++	Broad genetic differential diagnosis without obvious syndromic association, or previous negative panel testing
Genome sequencing	Genomic	+	+	+++	Broad genetic differential diagnosis without obvious syndromic association, or previous negative panel testing and need for rapid turnaround time

By lesion

Lesion

Pick a lesion to see its 22q11.2 and aneuploidy frequencies, the test to send and the syndromes listed with it.

Tetralogy of Fallot

Tetralogy of Fallot (TOF)

How often

Finding	Frequency	Source
22q11.2 deletion	8%–13%; strongest with pulmonary atresia	AHA 2018
22q11 deletion	8–35%	AHA 2014 Table 11
Aneuploidy	7–39%	AHA 2014 Table 10

Test

Reasonable to test every patient for the 22q11.2 deletion (AHA 2018 Table 3; fetuses when amniocentesis is done for diagnosis), by CMA (AHA 2018 text).
Nonsyndromic TOF with absent pulmonary valve, arch or pulmonary artery anomalies, or aortopulmonary collaterals: modestly increased diagnostic yields (overall <10%); lesion-specific recommendations may emerge (AHA 2021).

Listed with TOF

22q11.2 deletion syndrome (conotruncal defects), trisomy 18, trisomy 21 (less common), Alagille, CHARGE, Noonan, Kabuki and others.

Truncus arteriosus

How often

Finding	Frequency	Source
22q11.2 deletion	12%–35%	AHA 2018
22q11 deletion	35–40%; 32% in one series (text)	AHA 2014 Table 11
Aneuploidy	19–78%	AHA 2014 Table 10

Test

Reasonable to test every patient for the 22q11.2 deletion (AHA 2018 Table 3; fetuses when amniocentesis is done for diagnosis), by CMA (AHA 2018 text).
Refer to genetics: isolated CHD highly associated with specific syndromes (AHA 2018 Table 9 names truncus).

Listed with truncus

22q11.2 deletion syndrome, 22q11.2 duplication, 1q21.1 deletion, trisomy 8 mosaicism, VACTERL, Townes-Brocks.

Interrupted aortic arch

Interrupted aortic arch (IAA)

How often

Finding	Frequency	Source
22q11.2 deletion	22%–48%; more than half of type B, uncommon in type A	AHA 2018
22q11 deletion	50–90%	AHA 2014 Table 11
Aneuploidy	5–37% (coarctation or arch interruption)	AHA 2014 Table 10

Test

Reasonable to test every patient for the 22q11.2 deletion (AHA 2018 Table 3; fetuses when amniocentesis is done for diagnosis), by CMA (AHA 2018 text).
Refer to genetics: isolated CHD highly associated with specific syndromes (AHA 2018 Table 9 names IAA).

Listed with IAA

22q11.2 deletion syndrome (type B).

Ventricular septal defect

Ventricular septal defect (VSD)

How often

Finding	Frequency	Source
22q11.2 deletion	2% overall; higher with an aortic arch anomaly	AHA 2018
22q11 deletion	10% overall; 45% with an aortic arch anomaly	AHA 2014 Table 11

Test

Malalignment, conoseptal hypoplasia or perimembranous VSD with an arch anomaly: reasonable to test for the 22q11.2 deletion, by CMA (AHA 2018 Table 3).
Otherwise, no CHD-specific source read recommends routine testing for isolated VSD after birth (ACMG 2021, not CHD-specific, covers any congenital anomaly before age 1); if testing, CMA is the first-tier test to consider (NSGC 2021).

Listed with VSD

Named in more than 40 rows of AHA 2018 Table 5 and its Appendix, including trisomies 13, 18 and 21 and 22q11.2 deletion syndrome; see the full tables under By syndrome.

Atrioventricular septal defect

Atrioventricular septal defect (AVSD)

How often

Finding	Frequency	Source
Aneuploidy	46–73%	AHA 2014 Table 10
Trisomy 21	50% to 70% of fetuses with AVSD and normal situs	AHA 2014

Test

Trisomy 21 suspected: karyotype (NSGC 2021; AHA 2018 Table 1). Otherwise CMA.
Unbalanced AVSD or malposed great arteries: consider a heterotaxy panel with primary ciliary dyskinesia genes (NSGC 2021).

Listed with AVSD

Trisomy 21, 8p23.1 deletion, 3p25 deletion, CHARGE, Holt-Oram, Noonan, Smith-Lemli-Opitz and others.

Atrial septal defect

Atrial septal defect (ASD)

Test

No CHD-specific source read recommends routine testing for isolated ASD after birth (ACMG 2021, not CHD-specific, covers any congenital anomaly before age 1); if testing, CMA is the first-tier test to consider (NSGC 2021). No ASD frequency is given.
Holt-Oram features (thumb or radial defects, AHA 2018 Table 5): TBX5 testing (NSGC 2021). ASD with atrioventricular conduction delay: NKX2-5 is listed (AHA 2018 Table 8). Common atrium: Ellis-van Creveld (Table 5).

Listed with ASD

Named in more than 30 rows of AHA 2018 Table 5 and its Appendix; see the full tables under By syndrome.

HLHS and aortic stenosis

HLHS and left-sided lesions (AS, BAV)

How often

Finding	Frequency	Source
Aneuploidy (HLHS)	4–9%	AHA 2014 Table 10
Putatively pathogenic CNVs, single ventricle	13.9% of 223 vs 4.4% of controls	AHA 2018

Test

If testing, CMA is the first-tier test to consider; karyotype if Turner syndrome is suspected (NSGC 2021).
Relatives: many centers recommend a baseline echo for first-degree relatives of anyone with an isolated left-sided obstructive lesion (NSGC 2021).

Listed with HLHS, AS or BAV

Turner (45,X), Jacobsen (11q deletion: HLHS in 5%–10%), trisomies 13 and 18, Kabuki and others.

Coarctation

Coarctation of the aorta (CoA)

How often

Finding	Frequency	Source
Aneuploidy	5–37% (coarctation or arch interruption)	AHA 2014 Table 10

Test

If testing, CMA is the first-tier test to consider; karyotype if Turner syndrome is suspected (NSGC 2021). Turner aortic follow-up: Turner Syndrome Aortic Z-Scores.
Relatives: many centers recommend a baseline echo for first-degree relatives (isolated left-sided obstructive lesion, NSGC 2021).

Listed with CoA

Turner (45,X), Jacobsen, trisomy 18, Kabuki and others.

Transposition of the great arteries

Transposition of the great arteries (TGA)

How often

Finding	Frequency	Source
Aneuploidy	0%; text: rarely associated	AHA 2014 Table 10
22q11 deletion	<1%	AHA 2014 Table 11
22q11.2 deletion	Infrequent	AHA 2018

Test

Fetus: still offer testing with counseling; most results are negative (AHA 2014). After birth, if testing: CMA is the first-tier test to consider (NSGC 2021).

Listed with TGA

Trisomy 18, 1q21.1 duplication, Kabuki and others; trisomy 21 less common.

Double-outlet right ventricle

Double-outlet right ventricle (DORV)

How often

Finding	Frequency	Source
22q11.2 deletion	2%	AHA 2018
22q11 deletion	<5%	AHA 2014 Table 11
Aneuploidy	6–43% (DORV or conotruncal malformations)	AHA 2014 Table 10

Test

If testing, CMA is the first-tier test to consider (NSGC 2021).

Listed with DORV

Trisomy 18, trisomy 9 mosaicism, CHARGE and others.

Heterotaxy

How often

Finding	Frequency	Source
Aneuploidy	0% (heterotaxy or cardiosplenic syndromes); text: rarely associated	AHA 2014 Table 10
Clinically relevant CNVs	15% to 26%	AHA 2018
ZIC3	Up to 5% of males	AHA 2018
Primary ciliary dyskinesia	Features in 37% (one study)	AHA 2018

Test

CMA in all; strongly consider ZIC3, especially in males; consider evaluation for primary ciliary dyskinesia (multigene panel) (AHA 2018).
Complex defects such as unbalanced AVSD or malposed great arteries: consider a heterotaxy panel with ciliary dyskinesia genes (NSGC 2021).

Listed with heterotaxy

Trisomy 13, 22q11.2 deletion syndrome, CHARGE and syndromic ciliopathies in a minority; most cases are not part of a syndrome (AHA 2018).

Supravalvar aortic stenosis

Supravalvar aortic stenosis (SVAS)

How often

Finding	Frequency	Source
In Williams syndrome	SVAS is the most common lesion (75%)	AHA 2018 Table 4

Test

Consider testing for Williams syndrome (7q11.23 deletion) in every patient at diagnosis; also with peripheral pulmonary artery stenosis persisting beyond infancy, or coronary ostial stenosis, renal artery stenosis or middle aortic syndrome at any age (AHA 2018).
Isolated SVAS, with or without a family history: consider ELN analysis (yield about 3.4% in one study) (NSGC 2021).

Listed with SVAS

Williams-Beuren syndrome (7q11.23 deletion); ELN, nonsyndromic familial SVAS (AHA 2018 Tables 5, 8).

Valvar pulmonary stenosis

Valvar pulmonary stenosis (PS)

How often

Finding	Frequency	Source
In Noonan syndrome	PS in roughly 40%, often with dysplastic leaflets	AHA 2018
Aneuploidy	1–12% (PS or atresia with intact septum)	AHA 2014 Table 10

Test

Consider a RASopathy multigene panel with Noonan-spectrum features, another cardiovascular malformation, or specific extracardiac features (NSGC 2021); once a RASopathy is suspected, AHA 2018 calls a panel of all RASopathy genes likely the most cost-effective test.

Listed with PS

Noonan, cardiofaciocutaneous, Costello, Alagille, Williams (supravalvar) and others.

Branch pulmonary artery stenosis

Branch or peripheral pulmonary artery stenosis

How often

Finding	Frequency	Source
In Alagille syndrome	Two-thirds have peripheral or branch pulmonary stenosis or other arterial narrowing	AHA 2018

Test

Consider a diagnosis of Alagille syndrome with these findings, even without overt liver disease (AHA 2018). If other features suggest it, JAG1 testing, including deletions, may be considered, ideally with a geneticist (NSGC 2021).
Stenosis persisting beyond infancy: consider Williams syndrome testing (AHA 2018).

Listed with branch stenosis

Alagille (20p12, JAG1), Williams (7q11.23) and others.

Ebstein anomaly

How often

Finding	Frequency	Source
Aneuploidy	4–16% (tricuspid valve dysplasia including Ebstein)	AHA 2014 Table 10

Test

If testing, CMA is the first-tier test to consider (NSGC 2021); no Ebstein-specific test recommendation was found.

Listed with Ebstein

1p36 deletion (Appendix); MYH7, also linked to LVNC, HCM and DCM (AHA 2018 Table 8; NSGC 2021 Table 3). With a pathogenic MYH7 variant, NSGC 2021 advises predictive testing of first-degree relatives and ongoing cardiac screening of carriers.

All rows: aneuploidy and 22q11 deletion by lesion (AHA 2014 fetal statement, Tables 10 and 11)

Risk of aneuploidy with selected cardiac malformations (AHA 2014 fetal statement, Table 10)
Lesion	Risk, %
Atrioventricular septal defect	46–73
Coarctation/arch interruption	5–37
Double-outlet right ventricle/conotruncal malformations	6–43
Hypoplastic left heart syndrome	4–9
Heterotaxy/cardiosplenic syndromes	0
Pulmonic stenosis/atresia with intact septum	1–12
Transposition of great arteries	0
Tetralogy of Fallot	7–39
Truncus arteriosus	19–78
Tricuspid valve dysplasia (including Ebstein malformation)	4–16

Estimated 22q11 deletion frequency with selected cardiac defects (AHA 2014 fetal statement, Table 11, modified from the 2007 AHA genetics statement)
Lesion	Estimated frequency, %
Interrupted aortic arch	50–90
Ventricular septal defect (overall)	10
Ventricular septal defect with aortic arch anomaly	45
Truncus arteriosus	35–40
Tetralogy of Fallot	8–35
Isolated aortic arch anomaly	25
Double-outlet right ventricle	<5
Transposition of the great arteries	<1

When to refer to genetics

Indications (AHA 2018 Table 9)
Reason	Example
Known familial variant	Infant of a parent with long-QT syndrome
Pretest or posttest counseling	Anticipatory guidance after a positive result
Preconception or prenatal recurrence risk	Parent with CHD planning a pregnancy
Prenatal counseling for a fetal anomaly	Testing options for a fetus with CHD
Family history of CHD, other malformations, learning disability or multiple miscarriages	Three generations with AVSD
Isolated CHD highly associated with specific syndromes	Interrupted aortic arch, truncus arteriosus, etc
Suspected genetic syndrome	Intellectual or learning disability, autism, other cognitive impairment; dysmorphic features; short stature; congenital anomalies; endocrine abnormalities; hearing or visual impairment; neurological deficits

Adult

CHD with a family history of CHD or features of a genetic syndrome: referral for genetic evaluation is reasonable 2a C-EO

ACHD 2025

Recurrence risk

Isolated (nonsyndromic) CHD, % (AHA 2018 Table 10)
Defect	Father	Mother	1 sibling	2 siblings
ASD	1.5–3.5	4–6	2.5–3	8
AVSD	1–4.5	11.5–14	3–4	10
VSD	2–3.5	6–10	3	10
AS aortic stenosis	3–4	8–18	2	6
PVS pulmonary valve stenosis	2–3.5	4–6.5	2	6
TOF	1.5	2–2.5	2.5–3	8
CoA	2–3	4–6.5	2	6
PDA	2–2.5	3.5–4	3	10
HLHS	21 either parent		2–9*	6
TGA d-TGA	2 either parent		1.5	5
L-TGA congenitally corrected TGA	3–5 either parent		5–6	NR
EA Ebstein anomaly	NR	6	1	3
TrA truncus arteriosus	NR	NR	1	3
TA tricuspid atresia	NR	NR	1	3
PA pulmonary atresia	NR	NR	1	3

Key (Table 10): TA, tricuspid atresia; TrA, truncus arteriosus; PA, pulmonary atresia; NR, not reported or insufficient data.

Overall: about 3% with one affected child; 5% to 10% when a parent or >2 siblings are affected (AHA 2018).

Fetal echo in a later pregnancy (AHA 2014 Table 2, at 18–22 weeks)
Affected relative	Absolute risk, % live births; class, level
Mother	3–7 (all); 10–14 (AVSD); 13–18 (AS); <3 (TOF, d-TGA) I B
Father	2–3, may be slightly higher I B
Sibling	3; 8 for HLHS I B
Second-degree relative	<2 IIb B
Third-degree relative	≈1 III B
First- or second-degree relative with a mendelian syndrome linked to CHD	Up to 50 I C

Isolated left-sided obstructive lesion (BAV, AS, CoA, mitral atresia, HLHS): many centers recommend a baseline echo for first-degree relatives (NSGC 2021).

By syndrome: cardiac screening

% with CHD from AHA 2018 Table 5 or Appendix
Syndrome	CHD, %	Cardiac screening or care
Trisomy 21	40–50	Newborn: echo read by a pediatric cardiologist, even after a normal fetal echo (AAP 2022; AHA 2024). 12–21 y: examine yearly for acquired mitral and aortic valve disease; echo for fatigue, dyspnea or a new murmur or gallop (AAP 2022).
Noonan and other RASopathies	75 (Noonan)	Cardiology with echo and ECG at diagnosis; if normal, again every 5 years through childhood and adulthood (AHA 2018)
Holt-Oram	50	Screening ECG every year (AHA 2018)
Jacobsen (11q deletion)	56	Echo at baseline and as needed (AHA 2018)
22q11.2 deletion syndrome	74–85	Leukocyte-depleted, CMV-negative blood products; plan surgery around immune and calcium issues (AHA 2018)
Williams	80	Higher risk of anesthesia-related complications and sudden death (AHA 2018)
Turner (45,X)	23–35	Baseline echo (AHA 2018); aortic follow-up: Turner Aortic Z-Scores
Trisomy 13; trisomy 18	57–80; 80–90	Surgery decided case by case, not on the trisomy alone (AATS 2023) abstract

Marfan, Loeys-Dietz and other aortopathies: Aortopathy.

All rows: genes, loci and % CHD by syndrome (AHA 2018 Table 5, Appendix; ACHD 2025 Table 9)

Genes and loci associated with CHD (AHA 2018 Table 5; spellings as printed)
Syndrome	Gene(s)	Loci	Cardiac disease	CHD, %
Very commonly associated
Alagille	JAG 1, NOTCH2	20p12.2, 1p12-p11	PPS, TOF, PA	>90
CFC	BRAF, KRAS, MAP2K1, MAP2K2	7q34, 12p12.1, 15q22.31, 19p13.3	PVS, ASD, HCM	75
Cantu	ABCC9	12p12.1	PDA, BAV, HCM, CoA, PE, AS	75
Char	TFAP2B	6p12.3	PDA, VSD	58
CHARGE	CHD7	8q12	TOF, PDA, DORV, AVSD, VSD	75–85
Costello	HRAS	11p15.5	PVS, ASD, VSD, HCM, arrhythmias	44–52
22q11.2DS	TBX1	22q11.2 deletion	Conotruncal defects, VSD, IAA, ASD, VR	74–85
Ellis-van Creveld	EVC, EVC2	4p16.2, 4p16.2	Common atrium	60
Holt-Oram	TBX5	12q24.1	VSD, ASD, AVSD, conduction defects	50
Kabuki	KMT2D, KDM6A	12q13, Xp11.3	CoA, BAV, VSD, TOF, TGA, HLHS	50
Noonan	PTPN11, SOS1, RAF1, KRAS, NRAS, RIT1, SHOC2, SOS2, BRAF	12q24.13, 2p22.1, 3p25.2, 12p12.1, 1p13.2, 1q22, 10q25.2, 14q21.3, 7q34	Dysplastic PVS, ASD, TOF, AVSD, HCM, VSD, PDA	75
VACTERL association	Unknown		VSD, ASD, HLHS, PDA, TGA, TOF, TA	53–80
Williams-Beuren	7q11.23 deletion (ELN)	7q11.23	SVAS, PAS, VSD, ASD	80
Frequently associated
Carpenter	RAB23	6p11.2	VSD, ASD, PDA, PS, TOF, TGA	50
Coffin-Siris	ARID1B, SMARCB1, ARID1A, SMARCB1, SMARCA4, SMARCE1	6q25, 22q11, 1p36.1, 22q11.23, 19p13.2, 17q21.2	ASD, AVSD, VSD, MR, PDA, PS, DEX, AS	20–44
Cornelia deLange	NIPBL, SMC1L1, SMC3	5p13, Xp11.22, 10q25	PVS, VSD, ASD, PDA	33
Goldenhar	Unknown		VSD, PDA, TOF, CoA, conotruncal defects	32
Mowat-Wilson	ZEB2	2q22.3	VSD, CoA, ASD, PDA, PAS	54
Rubinstein-Taybi	CBP, EP300	16p13.3, 22q13.2	PDA, VSD, ASD, HLHS, BAV	33
Smith-Lemli-Opitz	DHCR7	11q12-13	AVSD, HLHS, ASD, PDA, VSD	50
Occasionally associated
Adams-Oliver	ARHGAP31, DOCK6, RBPJ, EOGT, NOTCH1, DLL4	3q13, 19p13.2, 4p15.2, 3p14.1, 9q34.3, 15q15.1	ASD, VSD, CoA, HLHS, DORV	20
Baller-Gerold	RECQL4	8q24.3	VSD, TOF, subaortic disease	25
Beckwith-Wiedemann	CDKNIC	11p15.4	VSD, HLHS, PS	6.5
Coffin-Lowry	RSK2	Xp22.2	LVNC, MVP, AVA	5–14
Duane-radial ray (Okihiro)	SALL4	20q13.2	ASD, PVS, VSD	<10
Fragile X	FMR1	Xq27.3	MVP, aortic dilation	<10
Nance-Horan	NHS	Xp22.13	TOF, VSD, PDA	<10
Peter’s Plus	B3GALTL	13q12.3	ASD, VSD, PVS, BPV, subvalvular AS	<30
Roberts	ESC02	8p21.1	ASD, AS	<20
Robinow	RDR2 (AR), WNT5A (AD)	9q22	RVOTO	29 AD; 13 AR
Saethre-Chotzen	TWIST	7p21p22	VSD	<10
Short rib polydactyly type I	DYNC2H1	11q22.3	TGA, DORV, DOLV, AVSD, HRH	<25
Simpson-Golabi-Behmel	GPC3	Xq26.2	TGA, VSD, PVS, CoA, AS, PDA, BAV, CM	26
Sotos	NSD1	5q35.3	ASD, PDA, VSD	21
Townes-Brocks	SALL1	16p12.1	ASD, TOF, VSD, TA, PA, PDA	14–25

Key (Table 5): TA, truncus arteriosus; PA, pulmonary atresia; PS and PVS, pulmonary stenosis; PAS, pulmonary artery stenosis; PPS, peripheral pulmonary stenosis; AVA, aortic valve anomaly; CM, cardiomyopathy; DEX, dextrocardia; DOLV, double-outlet left ventricle; HRH, hypoplastic right heart; PE, pericardial effusion; RVOTO, right ventricular outflow tract obstruction; VR, vascular ring; AD and AR, autosomal dominant and recessive; CFC, cardiofaciocutaneous.

Chromosomal aneuploidies and copy number variants (AHA 2018 Appendix)
Chromosome change	CHD, %	Heart anomaly
I. Aneuploidies (identifiable by routine karyotype)
Trisomy 8 mosaicism	25	VSD, PDA, CoA, PVS, TAPVR, TrA
Trisomy 9/mosaicism	65	PDA, LSVC, VSD, TOF/PA, DORV
Trisomy 13 (Patau syndrome)	57–80	ASD, VSD, PDA, HLHS, laterality defects, atrial isomerism
Trisomy 18 (Edwards syndrome)	80–90	ASD, VSD, PDA, TOF, DORV, TGA, CoA, BAV, BPV, polyvalvular nodular dysplasia
Trisomy 21 (Down syndrome)	40–50	AVSD, VSD, ASD, (TOF, TGA less common)
Monosomy X (Turner syndrome, 45,X)	23–35	CoA, BAV, AS, HLHS, aortic dissection
II. Chromosome abnormalities (identifiable on karyotype and more recently using chromosomal microarray)
3p25 deletion	33	VSD, AVSD, tricuspid atresia
Deletion 4p16.3 (Wolf-Hirschhorn syndrome)	50–65	ASD, VSD, PDA, LSVC, aortic atresia, dextrocardia, TOF, tricuspid atresia
Deletion 4q	50	VSD, PDA, AS, ASD, TOF, CoA
Deletion 5p (cri-du-chat)	30–60	VSD, ASD, PDA
Deletion 9p syndrome	35–50	VSD, PDA, PVS
Deletion 10p	42	BAV, ASD, VSD, PDA, PVS, CoA
Duplication 10q24-qter	50	AVSD, VSD
III. Copy number variants (identifiable by chromosomal microarray)
1p36 deletion	70	PDA, VSD, ASD, BAV, Ebstein anomaly, noncompaction cardiomyopathy
1q21.1 deletion	N/A	PDA, VSD, ASD, TrA, TOF
1q21.1 duplication	N/A	TOF, TGA, PVS
1q41q42 microdeletion	40	BAV, ASD, VSD, TGA
1q43q44 microdeletion	N/A	VSD, CoA, HLHS
2q31.1 microdeletion	25	VSD, ASD, PDA
2q37 microdeletion	30	VSD, ASD, CoA, hypoplastic aortic arch
Deletion 7q11.23(Williams-Beuren syndrome)	53–85	Supravalvar AS and PS, PPS
8p23.1 deletion	50–75	AVSD, PVS, VSD, TOF
9q34.3 Subtelomeric deletion (Kleefstra syndrome)	31–44	ASD, VSD, TOF, pulmonary arterial stenosis
Deletion 11q (Jacobsen syndrome)	56	HLHS, AS, VSD, CoA, Shone’s complex
15q24 microdeletion	40	PDA, pulmonary arterial stenosis, PVS
16p11.2p12.2 microdeletion	33	TOF, BAV, pulmonary atresia
17q21 microdeletion	27	PVS, ASD, VSD, BAV
Deletion 20p12 (Alagille syndrome)	85–94	Peripheral PA hypoplasia, TOF, PVS (left-sided heart lesions and septal defects less common)
22q11.2DS (DiGeorge, velocardiofacial, and conotruncal anomaly face syndrome)	75	IAA-B, TrA, isolated aortic arch anomalies, TOF, conoventricular VSD
22q11.2 duplication	15	TOF, HLHS, VSD, PVS, TrA
22q13 microdeletion (Phelan-McDermid syndrome)	>25	PDA, VSD, ASD, TAPVR

Key (Appendix): TrA, truncus arteriosus; PA, pulmonary artery; PS, pulmonary stenosis; PVS, pulmonic valve stenosis; PPS, peripheral pulmonary stenosis; IAA-B, interrupted aortic arch type B; TOF/PA, tetralogy of Fallot with pulmonary atresia; TGA, d-transposition of the great arteries; LSVC, persistent left superior vena cava; BPV, bicuspid pulmonary valve; TAPVR, total anomalous pulmonary venous return; N/A, not available.

Adult Genetic syndromes and CHD (ACHD 2025 Table 9, adult guideline; modified from Stout et al. 2018)
Syndrome	Genetic abnormality	CHD	Common cardiac findings
22q11.2 deletion syndrome (DiGeorge syndrome, velocardiofacial syndrome)	22q11.2 deletion	60%-80%	Interrupted aortic arch type B, other aortic arch abnormalities, truncus arteriosus, tetralogy of Fallot, ventricular septal defect/pulmonary atresia
Down syndrome	Trisomy 21	40%-50%	Atrial septal defect, ventricular septal defect, atrioventricular septal defect, tetralogy of Fallot
Holt–Oram syndrome	TBX5	75%	Atrial septal defect, ventricular septal defect, valvular disease (mitral valve prolapse, pulmonary stenosis)
Klinefelter syndrome	47,XXY	50%	Patent ductus arteriosus, atrial septal defect, mitral valve prolapse
Noonan syndrome	PTPN11, KRAS, SOS1, RAF1, NRAS, BRAF, MAP2K1	80%	Pulmonary stenosis, atrial septal defect, hypertrophic cardiomyopathy, atrioventricular septal defect
Turner syndrome	45,X	30%	Bicuspid aortic valve, coarctation of the aorta, aortopathies, partial anomalous pulmonary venous connection, atherosclerosis risk
Williams syndrome	7q11.23 deletion	50%-80%	Supravalvar aortic stenosis, branch pulmonary artery stenosis, supravalvar pulmonary stenosis, coronary ostial stenosis, QTc prolongation, mid-aortic narrowing syndrome
Alagille syndrome	JAG1	70%-75%	Two-thirds with peripheral or branch pulmonary artery stenosis or other arterial narrowing (coarctation of the aorta, renal artery stenosis, middle cerebral artery, Moyamoya); also can have tetralogy of Fallot, aortic stenosis, septal defects, mid-aortic narrowing syndrome
Heterotaxy syndrome	ZIC3, SHROOM3, GRK 5, ANKS3, NODAL, CFC1, LEFTY2, GDF1, SMAD2, ACVR2B	50%-95%	Atrioventricular septal defect (balanced, unbalanced), malposed great vessels, interrupted inferior vena cava, bilateral superior vena cava, atrial isomerism

Key points

Fetus with CHD: genetic counseling and an offer of aneuploidy testing (Class I, A; AHA 2014); amniocentesis with CMA offered (NSGC 2021).
After birth, if testing: CMA first; karyotype if a common trisomy or Turner is suspected (NSGC 2021). AHA 2018 suggests 22q11.2 deletion testing, by CMA, in every patient with IAA, truncus or TOF.
Exome or genome sequencing is now first- or second-tier for any anomaly before 1 year (ACMG 2021); CHD-specific statements still call it emerging.
Isolated CHD recurs in about 3% of later siblings, more often when the mother is affected (AHA 2018).

Sources and how this page was checked

Full text read

Pierpont ME, Brueckner M, Chung WK, et al.; American Heart Association Council on Cardiovascular Disease in the Young, et al. Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association. Circulation 2018;138(21):e653-e711. doi:10.1161/CIR.0000000000000606. Archived publisher copy (the corrected version) and the PMC author manuscript; the correction notice itself was not read. Scientific statement, no classes. Reflects 2018 practice.
Ison HE, Griffin EL, Parrott A, et al. Genetic counseling for congenital heart disease: practice resource of the National Society of Genetic Counselors. J Genet Couns 2022;31(1):9-33 (online 2021). doi:10.1002/jgc4.1498. Repository copy of the publisher’s PDF. Practice resource, no grades.
Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6. Archived publisher copy. GRADE, one strong recommendation; not specific to CHD.
Landstrom AP, Kim JJ, Gelb BD, et al.; American Heart Association Council on Genomic and Precision Medicine, et al. Genetic testing for heritable cardiovascular diseases in pediatric patients: a scientific statement from the American Heart Association. Circ Genom Precis Med 2021;14(5):e000086. doi:10.1161/HCG.0000000000000086. PMC author manuscript; no classes.
Donofrio MT, Moon-Grady AJ, Hornberger LK, et al. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation 2014;129(21):2183-2242. doi:10.1161/01.cir.0000437597.44550.5d. Archived publisher copy; its correction notice was not read. ACC/AHA classes.
Bull MJ, Trotter T, Santoro SL, et al.; Council on Genetics. Health supervision for children and adolescents with Down syndrome. Pediatrics 2022;149(5):e2022057010. doi:10.1542/peds.2022-057010. Archived publisher copy; clinical report, no grades.
Peterson JK, Clarke S, Gelb BD, et al. Trisomy 21 and congenital heart disease: impact on health and functional outcomes from birth through adolescence: a scientific statement from the American Heart Association. J Am Heart Assoc 2024;13(19):e036214. doi:10.1161/JAHA.124.036214. Open access; no classes.
Durbin MD, Fairman K, Helvaty LR, et al. Genetic testing guidelines impact care in newborns with congenital heart defects. J Pediatr 2023;260:113495. doi:10.1016/j.jpeds.2023.113495. PMC author manuscript. Single-centre cohort of 664 infants having heart surgery (2013–2018): testing rose from 39.9% to 75.3% after local guidelines; 41.9% of those tested had an abnormal result (38.0% isolated CHD, 53.9% with other anomalies).
Gurvitz M, Krieger EV, Fuller S, et al. (Writing Committee). 2025 ACC/AHA/HRS/ISACHD/SCAI guideline for the management of adults with congenital heart disease. Circulation 2026;153(8):e115-e251. doi:10.1161/CIR.0000000000001402. Archived publisher copy with the recommendation-table image (Section 3.7). Adult.

Abstract only

St Louis JD, Bhat A, Carey JC, et al. The American Association for Thoracic Surgery (AATS) 2023 expert consensus document: recommendation for the care of children with trisomy 13 or trisomy 18 and a congenital heart defect. J Thorac Cardiovasc Surg 2024;167(5):1519-1532. doi:10.1016/j.jtcvs.2023.11.054. The abstract reports nine recommendations, usually Class IIa and level C-LD; none is shown individually.

Not read for this page

De Backer J, Bondue A, Budts W, et al. Genetic counselling and testing in adults with congenital heart disease: a consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Eur J Prev Cardiol 2020;27(13):1423-1435. doi:10.1177/2047487319854552. Adult.
Care M, Arbour L, Brunham LR, et al. Canadian Cardiovascular Society clinical practice update on cardiogenetic testing. Can J Cardiol 2025;41(12):2312-2333. doi:10.1016/j.cjca.2025.08.364. All ages, Canadian.
Syndrome-specific guidelines (22q11.2 deletion syndrome 2023, Williams syndrome): this page states no surveillance interval for those syndromes.

How it was checked

Numbers are copied from the sources (November 2026); wording is condensed. AHA 2014 tables print values under a % heading; they are shown with %. Ranges keep each source’s style (ACHD 2025 prints “60%-80%”). Terms follow each source: CMA, FISH, ES/GS, 22q11.2 deletion syndrome (AHA 2018), 22q11 deletion (AHA 2014).
Reproduced in full: AHA 2018 Tables 1, 9 (condensed wording), 10 and 5 and its Appendix (35 syndrome and 31 chromosomal rows), AHA 2014 Tables 10 and 11, ACHD 2025 Table 9 (clinical-features column left out). Graded rows: 7 from AHA 2014 (one recommendation, six Table 2 rows) and the 2 ACHD 2025 genetics recommendations. The “listed with” names in each lesion panel are every row of AHA 2018 Tables 5 and 8 and the Appendix that names that lesion, read with each table’s own abbreviations; Table 8 entries abbreviated PVS are not used because its footnote defines PVS as pulmonary vein stenosis while Table 5 defines it as pulmonary stenosis.
Sources differ: 22q11.2 deletion frequencies (AHA 2018 text: IAA 22%–48%, truncus 12%–35%, TOF 8%–13%, VSD 2%; AHA 2014 Table 11: 50–90, 35–40, 8–35, 10); recurrence (AHA 2018 Table 10, AHA 2014 Table 2, NSGC 2021 Figure 3); % CHD by syndrome (see the tip on that table); the first test (AHA 2018 Table 1 lists FISH for 22q11.2 deletion and karyotype for trisomy 21, while its text and NSGC 2021 put CMA first). Highest recurrence: NSGC 2021 names left-sided obstructive lesions as the class with the highest recurrence risk; AHA 2018 gives the highest same-defect relative risks for heterotaxy (79.1) and RVOT defects (48.6), with LVOT obstruction 12.9. Ciliary dyskinesia: NSGC 2021 Table 3 gives 12% of heterotaxy patients, while AHA 2018 says at least 12.1% of patients with classic primary ciliary dyskinesia have heterotaxy (the reverse direction); neither is shown in the panel. Each difference is shown side by side or stated here, not reconciled.
As printed: AHA 2018 Table 3 says “interruption of aortic arch”, its text “IAA type B”. AHA 2018 Table 5 spellings are kept (e.g. JAG 1, CDKNIC, ESC02, RDR2). AHA 2014 reports one series with aneuploidy in AVSD (80%), coarctation (49%), “TOF, and ventricular septal defects (45%)”; it is not shown. Durbin 2023 prints the 2018 odds ratio interval as 2.84–8.88 in the abstract and 2.84–8.98 in the results.
The field is moving: the CHD statements reflect 2014 (fetal), 2018 and 2021 practice, before routine exome or genome sequencing; ACMG 2021 is the only first-tier exome/genome recommendation found, and it is not CHD-specific.

Which test first

By lesion

Tetralogy of Fallot (TOF)

How often

Test

Truncus arteriosus

How often

Test

Interrupted aortic arch (IAA)

How often

Test

Listed with IAARows naming IAA. AHA 2018 Table 5: 22q11.2DS. Appendix: 22q11.2DS (DiGeorge, velocardiofacial, and conotruncal anomaly face syndrome).

Ventricular septal defect (VSD)

How often

Test

Listed with VSD

Atrioventricular septal defect (AVSD)

How often

Test

Listed with AVSDRows naming AVSD. AHA 2018 Table 5: CHARGE, Holt-Oram, Noonan, Coffin-Siris, Smith-Lemli-Opitz, Short rib polydactyly type I. Appendix: Trisomy 21 (Down syndrome); 3p25 deletion; Duplication 10q24-qter; 8p23.1 deletion. Table 8, nonsyndromic genes: GATA4, NR2F2, ACVR1/ALK2, CRELD1.

Atrial septal defect (ASD)

Test

Listed with ASD

HLHS and left-sided lesions (AS, BAV)

How often

Test

Coarctation of the aorta (CoA)

How often

Test

Transposition of the great arteries (TGA)

How often

Test

Listed with TGARows naming TGA. AHA 2018 Table 5: Kabuki, VACTERL association, Carpenter, Short rib polydactyly type I, Simpson-Golabi-Behmel. Appendix: Trisomy 18 (Edwards syndrome); Trisomy 21 (Down syndrome); 1q21.1 duplication; 1q41q42 microdeletion. Table 8, nonsyndromic genes: MED13L.

Double-outlet right ventricle (DORV)

How often

Test

Listed with DORVRows naming DORV. AHA 2018 Table 5: CHARGE, Adams-Oliver, Short rib polydactyly type I. Appendix: Trisomy 9/mosaicism; Trisomy 18 (Edwards syndrome). Table 8, nonsyndromic genes: ZFPM2/FOG2.

Heterotaxy

How often

Test

Listed with heterotaxy

Supravalvar aortic stenosis (SVAS)

How often

Test

Listed with SVAS

Valvar pulmonary stenosis (PS)

How often

Test

Branch or peripheral pulmonary artery stenosis

How often

Test

Ebstein anomaly

How often

Test

Listed with Ebstein

When to refer to genetics

Recurrence risk

By syndrome: cardiac screening

Key points

Related on HeartCalc

Full text read

Abstract only

Not read for this page

How it was checked

Listed with IAA

Listed with AVSD

Listed with TGA

Listed with DORV