SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis

Figures & data

Table 1 Chromosomal Abnormalities Detected in Fetuses with Congenital Heart Disease Revealed by Prenatal Echocardiography

Subjects Grouping	No. of Fetuses	Proportion of Chromosomal Abnormality (%)	No. of Fetus with Trisomy 18	No. of Fetus with Trisomy 21	No. of Fetus with Trisomy 13	No. of Fetus with Abnormal Chromosome Number	No. of Fetus with Chromosomal Structural Abnormality
Single cardiac malformation	142	5.6	0	3	0	1 (47,XYY)	4 (46,XX,add(1)(q42); 46,XY,del(4)(q25q28); 46,XY,del(21)(q22); 46,X,add(Y)(q11))
Multiple cardiac malformation	106	4.7	1	1	0	0	3 (46,XY,del(2)(q37); 46,XX,add(8)(q21); 46,XX,add(18)(p11))
Cardiac and extracardiac malformations	108	18.5	9	4	2	2 (47,XY,+21)	3 (46,XY,del(4)(p14); 46,XY,del(5)(p14.3); 46,XY,add(22)(q11.1))
Total	356	9.3	10	8	2	3	10

Table 2 SNP Array Findings in Fetuses

Group	Fetus No.	Ultrasound Findings	SNP Array Findings (NCBI build37(hg19))	Type of CNVs	Fragment Size (Mb)	Pregnancy Outcomes
Single cardiac malformation	1	Ventricular septal defect	arr[hg19]3q29(195,743,957–197,386,180) ×3	Pathogenic	1.6	Induction of labor
	2	Lack of clear continuity in the membranous part of interventricular septum	arr[hg19] 16p11.2(29,580,020–30,30 2,348) ×3	Pathogenic	0.7	Induction of labor
	3	Ventricular septal defect	arr[hg19]Xq28(152,713,658–153,421,838)×3	Pathogenic	0.7	Induction of labor
	4	Pulmonary artery dilation after stenosis	arr[hg19]18q23(73,969,018–78,013,728)x1,22q13.33(49,571,996–51,197,766) ×3	Pathogenic	1.6	Induction of labor
	5	Ventricular septal defect	arr[hg19]9q21.33q22.1(89,868,507–90,975,015) ×3	VOUS	1.1	Birth, good growth and development
	6	Ventricular septal defect	arr[hg19]16p13.11(14,897,401–16,534,031) ×1	VOUS	1.6	Birth, good growth and development
Multiple cardiac malformation	7	Ventricular septal defect, right aortic arch and U-shaped vascular ring	arr[hg19]22q11.21(18,648,855–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	8	Aortic stenosis, ventricular septal defect and interruption of the aortic arch (type B)	arr[hg19] 22q11.21(18,631,364–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	9	Ventricular septal defect, mirror right aortic arch and right artery catheterization	arr[hg19] 22q11.21(18,916,842–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	10	Foramen ovale valve aneurysm, smaller left heart than right heart, small ascending aorta and aortic arch	arr[hg19]22q11.21(18,649,189–21,800,471)×3	Pathogenic (22q11.2 microduplication syndrome)	3.1	Induction of labor
	11	Ventricular septal defect, aorta overriding and pulmonary artery stenosis	arr[hg19] 8p22(17,179,780–18,518,478) ×3	Pathogenic	1.3	Induction of labor
	12	Right aortic arch with mirror-image branching and right artery catheterization	arr[hg19]17p11.2(16,615,982–18,922,171) ×3	Pathogenic (17p11.2 microduplication syndrome)	2.3	Induction of labor
	13	Right dominant heart and persistent right umbilical vein	arr[hg19]1q21.1q21.2(145,084,525–147,885,600) ×1	Pathogenic	2.8	Induction of labor
	14	Narrow right ventricle, tricuspid valve stenosis and insufficiency, pulmonary artery stenosis, and reverse supply of arterial arch blood flow to left and right pulmonary arteries (hypoplastic right heart)	arr[hg19]1q21.1q21.2(145,995,176–147,398,268) ×3	VOUS	1.4	Induction of labor
	15	Childbearing history of tetralogy of Fallot, ventricular septal defect, enlargement of the foramen ovale	arr[hg19]2q31.2q31.3(180,558,684–181,901,189) ×3	VOUS	1.3	Birth, ventricular septal defect and surgical repair
	16	Ventricular septal defect, aorta overriding, moderate stenosis of pulmonary artery, and right aortic arch with mirror-image branching	arr[hg19]15 q13.3(32,003,537–32,444,043) ×3	VOUS	0.4	Induction of labor
Cardiac and extracardiac malformations	17	Fetal growth restriction and ventricular septal defect	arr[hg19]22q11.21(18,648,855–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	18	Fallot’s malformation and thymic hypoplasia	arr[hg19]22q11.21(18,648,855–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	19	Ventricular septal defect, aorta overriding, pulmonary artery stenosis, few pericardial effusion, separation of bilateral renal pelvis, persistent right umbilical vein and conusmedullaris level at L4	arr[hg19] 22q11.21(18,631,364–21,800,471) ×1	Pathogenic (22q11.2 microdeletion syndrome)	3.1	Induction of labor
	20	Anterior nasal skin thickening,left axis deviation of the heart, and ventricular septal defect	arr[hg19] 2q37.3(241,000,861–242,782,258) ×1, 22q13.2q13.33(41,122,658–51,197,766) ×3	Pathogenic	1.8	Induction of labor
	21	Ventricular septal defect, enlargement of the atrium dextrum and vetrauriculadextra, persistent left superior vena cava, vagus of the right subclavian artery, Blake’s pouch cyst and fetal nuchal fold thickening	arr[hg19] 2q13(111,397,196–113,111,856) ×1	Pathogenic	1.7	Induction of labor
	22	Fetal growth restriction and pulmonary valve stenosis	arr[hg19]4p16.3 p16.1(68,345–6,608,624) ×1	Pathogenic	6.5	Induction of labor
	23	Ventricular septal defect and left renal agenesis	arr[hg19]7q11.23(72,701,098–74,069,645) ×3	Pathogenic	1.3	Induction of labor
	24	Wider fetal pulmonary artery than aorta, fetal nuchal fold thickening	arr[hg19] 7q11.23(72,713,282–74,154,209) ×1	Pathogenic	1.4	Induction of labor
	25	Ventricular septal defect, brain dysplasia and Dandy–Walker malformation	arr[hg19]15q11.2(22,770,421–23,277,436) ×1	Pathogenic	0.5	Induction of labor
	26	Fetal growth restriction, ventricular septal defect, nasal bone hypoplasia, pulmonary artery valve stenosis and insufficiency	arr[hg19]15 q24.1q24.2(72,965,465–75,567,135) ×1	Pathogenic	2.6	Induction of labor
	27	Ventricular septal defect, aorta overriding, pulmonary artery stenosis, single umbilical artery	arr[hg19]16p12.3(19,333,917–20,487,932) ×1	Pathogenic	1.1	Induction of labor
	28	Dilation of lateral ventricle, fetal growth restriction, ventricular septal defect, persistent left superior vena cava	arr[hg19]16p13.3(85,880–536,631) ×1	Pathogenic	0.4	Induction of labor
	29	Fetal growth restriction, persistent left superior vena cava, narrowing of the interior diameter of the aortic arch, slightly enhanced echo of the bilateral renal parenchyma, battledore-like placenta, placental thickening and placental blood pool	arr[hg19]2p25.3p11.2(50,813–87,053,152)hmz, 2q11.1q37.3(95,550,957–242,773,583) hmz	Pathogenic	h UPD	Induction of labor
	30	Fetal growth restriction, ventricular septal defect, aortic stenosis, hypoplasia or agenesis of the left kidney, echogenic bowel	arr[hg19]16q23.3q24.3(79,800,878–90,146,366)hmz, 16p13.3p12.3(94,807–19,302,326)hmz	Pathogenic	UPD	Induction of labor
	31	Ventricular septal defect and fetal growth restriction	arr[hg19]4q24(106,284,925–107,545,257) ×3	VOUS	1.2	Birth, ventricular septal defect, surgical repair
	32	Ventricular septal defect, right hydronephrosis, broadening of the left ventricle and broadening of the cerebellomedullary cistern	arr[hg19]11p15.1p14.3(20,745,930–21,780,075) ×3	VOUS	1.0	Induction of labor

Abbreviations: VOUS, variant of unknown significance; CNV, copy number variation.

Table 3 Abnormal Copy Number Variations Detected in Fetuses

Subjects Grouping	No. of Fetuses	Total Fetuses with Abnormal CNVs (Proportion)	Pathogenic CNVs	VOUS
Single cardiac malformation	142	6 (4.2%)	4	2
Multiple cardiac malformation	106	10 (9.4%)	7	3
Cardiac and extracardiac malformations	108	16 (14.8%)	14	2
Total	356	32 (9.0%)	25	7

Abbreviations: CNV, copy number variation; VOUS, variants of unknown significance.