Table 3.
CNV screens in patients with heart defects
| Patients | Phenotype of patientsd | Microarray type | Main results | Candidate genes in CNVsg | Reference |
|---|---|---|---|---|---|
| 60 | Congenital heart disease and extracardiac abnormalities | In-house-made microarray containing BAC/PACe clones. Average genomic distance of probes were 1 Mbp | CNVs considered to be causal were identified in 10 (17 %) patients | EHMT1, NKX2-5, NOTCH1, NSD1 | [233] |
| 105 | Congenital heart disease with and without extracardiac abnormalities. Subjects with documented syndromes were excluded | In-house-made microarray containing 32 k overlapping BAC clones | Rare de novo or inherited CNVs (0.34–13.9 Mb in size) were detected in 18 (17 %) patients | GJA5, LTBP1, TBX1 | [222] |
| 40 | Congenital heart disease with and without extracardiac abnormalities | NimbleGen Systems, Inc. whole-genome 385 K oligo array | Seven large CNVs were identified in 5 (12.5 %) patients | N/A | [230] |
| 114 | Tetralogy of Fallot (TOF) | Affymetrix Genome-Wide Human SNP Array 6.0 | Eleven (9.6 %) rare de novo CNVs (>20 kb) were identified in 114 TOF trios | JAG1, NOTCH1, RAB10, RAF1, TBX1 | [225] |
| 150a | Congenital heart disease and extracardiac abnormalities | In-house-made microarray containing BAC/PAC clones. Average genomic distance of probes were 1 Mbp | CNVs considered to be causal were identified in 26 (17.3 %) patients | ATRX, CREBBP, EHMT1, FOXC1, GATA4, NOTCH1, RAI, TBX1 | [220] |
| 46 | Isolated congenital heart disease | Affymetrix Genome-Wide Human SNP Array 6.0 | De novo CNVs were identified in two (4 %) patients | GJA5, NOTCH1, PDGFRA, TBX1 | [221] |
| 58 | Congenital heart disease and extracardiac abnormalities | Affymetrix GeneChip 100 K microarray | Potentially pathogenic CNVs (0.2–9.6 Mb in size) were detected in 12 (20.7 %) patients | ADAM19, HAND1, MESP1, NRP1, NTRK | [224] |
| 53 | Hypoplastic left heart syndrome (HLHS) | Agilent customized genome-wide 400 K array | Thirty-three rare non-polymorphic CNVs (2–1,554 kb in size) were detected in 25 (47 %) patients | BMPR2, ZNF423 | [227] |
| 262 | Heterotaxy (patients with D-transposition of the great arteries were also included in the sample) | Illumina 610Quad Beadchip platform | Forty-five previously unrecorded genic CNVs (0.27–25 Mb in size) were identified in 39 (14.5 %) patients. A significant (p = 1.5e − 4) burden of rare genic CNVs were found in HTX cases (14.5 %) compared to controls (7.4 %) | GALNT11, NEK2, NUP188, ROCK2, TGFBR2 | [223] |
| 43 | HLHS | NimbleGen Systems, Inc. whole-genome 385 K oligo array | A significant (p < 0.03) burden of CNVs were found in patients (4.6/subject) compared to controls (2.94/subject). The burden of unique CNVs in CHD patients was not found to be significant | N/A | [229] |
| 67b | Left-sided congenital heart disease (BAV, AS, COA, HLHS) | Affymetrix Human Genome-Wide SNP Array 6.0 | A total of 73 unique inherited or de novo CNVs (>20 kb) were identified in 54 individuals | ADORA2B, ANG, CACNA1C, COPS3, CRMP1, CTHRC1, ERCC5, EVC2, FLII, GRPEL1, HSD17B10, ITGA10, LIMS1, MAPK7, MFAP4, MSX1, MTHFD2, NCOR1, NGEF, PLA2G12A, PRPSAP2, RASD1, SBEBF1, SMC1A, ULK2 | [226] |
| 2,539 | Isolated congenital heart disease (808 TOF and 1,448 other CHDs). Subjects with documented syndromes known to cause CHD were excluded | Illumina 660 W-Quad SNP platform | A significant (p = 0.008) burden of rare genic CNVs were found in CHD cases (7.8 %) compared to controls (4.4 %) | CNOT6, EDIL3, GATA4, GJA5, HAND2, PPM1K and 13 genes in the WNT-signaling pathway (CDH18, CDH2, CTBP1, CTNNB1, FAT1, LRP5L, NFATC1, PCDH15, PCDHB7, PCDHB8, PRKCB, PRKCQ, WNT7B) | [232] |
| 203 + 511c | Congenital heart disease and extracardiac abnormalities. | Customized 105 k oligonucleotide arrays manufactured by Agilent. Average resolution of 30 kb, with denser coverage at disease loci | A total of 55 rare CNVs (>50 kb) were identified in patients from the discovery cohort. Sixteen of these CNVs were identified in the second cohort | PDE1A, NALCN, ANKRD11, SOX7, GATA4, CRK, CAMTA2, CECR1 | [228] |
| 433 | Tetralogy of Fallot-pulmonary atresia or pulmonary atresia and ventricular septal defect. Subjects with documented syndromes were excluded | Affymetrix Genome-Wide Human SNP Array 6.0 | 47 large (>500 kb) rare CNVs were found in 43 (9.9 %) patients | ANGPT2, ARHGEF10, ARHGEF4, BARD1, BBS9, C12oerf66, CASP1, CASP12, CASP4, CASP5, CCDC148, CDH19, CHL1, CHRM3, CHST8, CNDP2, CNN2, CRKL, DISP1, DNAH11, EDIL3, FGF10, FOXO3B, FSTL3, FSTL4, GJA5, GMDS, GNA11, HIRA, HNF1B, HRIP3, IDS, KCNB2, KIAA1609, LBH, MAPK3, NBEA, NFATC1, NXN, PARD6G, PDS5B, PLXNA2, PPM1K, PPP4C, PTBP1, RAF1, S1PR4, SEMA3D, SEMA3E, SFPQ, SLC25A46, SNX8, SOX4, SPG20, TBX1, TBX6, TNFSF11, VCAN, WDR18, WNK3, ZNF347 | [231] |
| 945 | Congenital heart disease with and without extracardiac abnormalities | Affymetrix Genome-Wide Human SNP Array 6.0 | Known CHD-related chromosomal abnormalitiesf were identified in 135 (14.3 %) patients. Large, rare CNVs (0.22–32.1 Mb in size) were identified in 35 (3.7 %) patients | FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA, MID1, PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6, RUNX1 | [234] |
Genes known to cause CHD in humans are underlined, genes with reported cardiovascular system involvement (e.g., from targeted deletion in mice) are bold
aIncludes 60 patients from Thienpont et al. [233]
bA total of 174 patients from 67 families
cA discovery cohort of 203 patients and a second independent cohort of 511 patients were analyzed
d AS aortic stenosis, BAV bicuspid aortic valve, COA coarctation of the aorta, HLHS hypoplastic left heart syndrome, TOF tetralogy of Fallot
e BAC bacterial artificial chromosome, PAC P1-derived artificial chromosome
fTrisomy 21 (n = 80), trisomy 18 (n = 1), 22qDS (n = 42), Turner syndrome (n = 8), William’s syndrome (n = 3), and Triple X syndrome (n = 1)
gCandidate genes suggested by the authors