Genetic testing in congenital heart disease: A clinical approach

Table 1 Genes described in syndromic and non-syndromic forms of congenital heart disease

Syndromic: Syndrome name Non syndromic: Gene implicated	Phenotype associated with structural heart disease	Syndromic: Chromosomal aneuploidy, microdeletion or gene/locus/inheritance Non syndromic: Locus/inheritance	Ref.
Atrioventricular septal defect (AVSD)
Down syndrome1	MR, facial dysmorphia	Trisomy 21	[71-73]
Edward syndrome	IUGR, facial dysmorphia, clenched fingers	Trisomy 18	[74]
Patau syndrome	Cleft lip and palate, microphthalmia, polydactyly	Trisomy 13	[74]
Holt-Oram syndrome	Preaxial limb defects, absent or dysmorphic thumbs, cardiac conduction disease	TBX5/12q24.1/AD	[75]
Noonan syndrome	Hypertrophic cardiomyopathy, short stature, broad neck, unusual chest shape, facial dysmorphia, developmental delay	PTPN11/12q24/AD, de novo; SOS1/2p21/AD, de novo; KRAS /12p12.1/AD, de novo	[76]
Ellis-van Creveld syndrome	Common atrium, polydactyly, deformity of upper lip, dwarfism with narrow thorax, ASVD partial to complete	EVC and EVC2/4p16/AR	[77]
Locus 1p31-p21	AVSD partial to complete	Gene no yet found/AD	[78]
CRELD1	Partial AVSD, heterotaxy syndrome	3p25/AD	[79-81]
GATA4	Family with ASD, VSD and one member with AVSD	8p23.1/AD, de novo	[82]
Atrial septal defect (ASD)
Holt Oram syndrome	See AVSD above	See above AVSD	[83,84]
Noonan syndrome	See AVSD above	See above AVSD	[85,86]
Ellis-van Creveld syndrome	See AVSD above	See above AVSD	[77]
Cardiofaciocutaneous syndrome	Hypertrophic cardiomyopathy, facial dysmorphia, skin abnormalities: keratosis pilaris, nevi	MAP2K1/15q22.31/AD, de novo; MAP2K2 /19p13.3/AD, de novo; KRAS/7q34/AD, de novo; BRAF/12p12.1/AD, de novo	[87]
Cri du Chat	Sound of cry similar to cat’s cry, facial dysmorphia, MR	CTNND2/5p15.2/de novo	[88]
NK2X-5	+/- Atrioventricular block	5q35.1/AD	[89]
GATA4	+/- Pulmonary stenosis	8p23.1/AD, de novo	[82,90]
MYH6		14q11.2/AD	[13]
TBX20		7p14.2/AD	[14,91]
Ventricular septal defect (VSD)
Holt Oram syndrome	See AVSD above	See AVSD above	[92]
Ellis-van Creveld syndrome	See AVSD above	See AVSD above	[77]
Cri du chat	See AVSD above	See AVSD above	[88]
Down syndrome	See AVSD above	See AVSD above	[93,94]
Edward/Patau syndrome	See AVSD above	See AVSD above	[95,96]
DiGeorge syndrome	Facial dysmorphia, speech delay, learning delay, psychiatric disorder, cleft palate, immune deficiency, hypoplastic/aplastic thymus, hypocalcaemia.	Deletion 22q11.21/de novo, AD	[97]
NK2X-5	Atrioventricular block	5q35.1/AD	[89]
GATA4		8p23.1/AD, de novo	[82,98]
Ebstein anomaly
Down syndrome	See AVSD above	See AVSD above	[99]
NKX2-5		5q35.1/AD	[100]
Pulmonary stenosis
Noonan syndrome1	See ASVD above	See AVSD above	[101,102]
Costello syndrome	Hypertrophic cardiomyopathy, MR, loose skin, facial dysmorphia large mouth	HRAS/11p15.5/AD	[103]
Leopard syndrome	Lentigines, short stature, hearing loss, similar to Noonan syndrome	PTPN11/12q24/AD, de novo; RAF1/3p25.2 /AD, de novo; BRAF/7q34/AD, de novo	[104]
Alagille syndrome	Pulmonary branch stenosis, bile duct paucity, cholestasis, facial dysmorphia, deep-set eyes, butterfly vertebrae	JAG1/20p12/AD; NOTCH2/1p12/AD; Deletion/20p12/AD	[105,106]
Cardiofaciocutaneous syndrome	See ASD above	See ASD above	[107]
GATA4	+/- Atrial septal defect	8p23.1/AD, de novo	[90, 108]
Aortic valve stenosis
Turner syndrome1	Female, webbed neck, widely spaced nipples, short stature, streaked ovaries	Monosomy X or mosaics (45,X/46,XX)	[109]
Noonan syndrome	See above AVSD	See above AVSD	[76]
NOTCH1		9q34.3/AD	[16, 110]
SMAD6		15q22.31/?	[111]
Supravalvular aortic stenosis
Williams-Beuren syndrome1	Elfin facies, cocktail personality, hypercalcaemia, developmental delay, thyroid disorder, renal and connective tissue abnormalities.	Deletion/7q11.23/de novo, AD	[112]
Aortic coarctation
Turner syndrome1	See aortic valve stenosis above	See aortic valve stenosis above	[109]
Down/Edward/Patau syndrome	See AVSD above	See AVSD above	[113]
NOTCH1		9q34.3/AD	[110]
Bicuspid aortic valve
Turner syndrome	See aortic valve stenosis above	See aortic valve stenosis above	[109]
Anderson syndrome	Long QT syndrome, ventricular arrhythmias, sudden cardiac death, facial dysmorphia, short stature	KCNJ2/17q24.3/AD	[114]
NOTCH1		9q34.3/AD	[16,110]
SMAD6		15q22.31/?	[111]
Tetralogy of Fallot
DiGeorge syndrome1	See VSD above	See VSD above	[97]
Alagille syndrome	See pulmonary stenosis above	See pulmonary stenosis above	[105,106]
Cat-Eye syndrome	Dysmorphic ears, microphthalmia, anal atresia, renal abnormalities, coloboma, cleft palate	Duplication/22q11/de novo	[115]
NKX2.5		5q35.1/AD	[100]
GATA4		8p23.1/AD, de novo	[116]
NOTCH1		9q34.3/AD	[16]
FOG2		8q23.1/?	[117,118]
Truncus arteriosus
DiGeorge syndrome	See VSD above	See VSD above	[97]
Hypoplastic left heart syndrome
NKX2.5		5q35.1/AD	[119]
NOTCH1		9q34.3/AD	[16,110]

¹The phenotype syndrome most commonly associated with the particular CHD.

AVSD: Atrioventricular septal defect; ASD: Atrial septal defect; VSD: Ventricular septal defect; MR: Mental retardation; IUGR: Intrauterine growth retardation; AD: Autosomal dominant; AR: Autosomic recessive; CHD: Congenital heart disease.

Table 2 Recurrence risks for non-syndromic congenital heart disease in first-degree relatives

Type of non-syndromic CHD	Recurrence risk of same CHD in first-degree relatives (%)	Recurrence risk of discordant CHD in first-degree relatives (%)	Recurrence risk of any CHD in first-degree relatives (%)
ASVD	1.10	2.2	3.30
ASD	0.88	2.4	3.28
VSD	0.67	1.9	2.57
ASD and VSD	0.24	2.2	2.44
Conotruncal defect1	1.30	2.4	3.70
Right ventricular outflow tract obstruction2	1.70	3.0	4.70
Left sided obstructions3	0.79	2.4	3.19

The recurrence risks for non-syndromic CHD in first-degree relatives are derived from a Danish cohort study[10,56].

¹Tetralogy of fallot, truncus arteriosus, interrupted aortic arch, double outlet ventricle, transposition of the arteries;

²Pulmonary valve stenosis, infundibular or subvalvular stenosis, double chambered right ventricle;

³Bicuspid aortic valve, aortic coartaction, aortic stenosis, hypoplastic left heart, shone complex. First-degree relatives include parents, siblings and twins; CHD: Congenital heart disease; ASVD: Atrioventricular septal defect; ASD: Atrial septal defect; VSD: Ventricular septal defect.