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.