Genomic imbalances in syndromic congenital heart disease<sup>,</sup>

Molck, Miriam Coelho; Simioni, Milena; Vieira, Társis Paiva; Sgardioli, Ilária Cristina; Monteiro, Fabíola Paoli; Souza, Josiane; Fett-Conte, Agnes Cristina; Félix, Têmis Maria; Monlléo, Isabella Lopes; Gil-da-Silva-Lopes, Vera Lúcia

doi:10.1016/j.jped.2016.11.007

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Original articles • J. Pediatr. (Rio J.) 93 (5) • Sep-Oct 2017 • https://doi.org/10.1016/j.jped.2016.11.007 copy

Genomic imbalances in syndromic congenital heart disease^☆ ☆ Please cite this article as: Molck MC, Simioni M, Vieira TP, Sgardioli IC, Monteiro FP, Souza J, et al. Genomic imbalances in syndromic congenital heart disease. J Pediatr (Rio J). 2017;93:497–507. ^,^☆☆ ☆☆ Study conducted at Universidade Estadual de Campinas (UNICAMP), Departamento de Genética Médica, Campinas, SP, Brazil.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective:

To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS).

Methods:

78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA).

Results:

Clinically significant copy number variations (CNVs ≥300 kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993 kb duplication in 15q21.1 and 706 kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD.

Conclusion:

These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD.

KEYWORDS
DNA copy number variations; Congenital heart defects; 22q11 deletion syndrome; Comparative genomic hybridization; Chromosome aberrations

ID	Type of CHD	CNV	Location	CNstate	Start (bp)	Stop (bp)	Size (kb)	RefSeq genes	DGV	DECIPHER	Validated by aCGH
2	ASD	del	12p12.1-p12.2	1	20,994,908	21,415,634	421	SLCO1B3, SLCO1B7, SLCO1B1	+	+	Yes
3	ASD	dup	15q22.2	3	62,209,640	62,543,660	334	VPS13C, C2CD4A, C2CD4B	-	+	NP
8	ToF, IAA	del	16p11.2	1	29,567,295	30,177,916	611	SLC7A5P1, SPN, QPRT, ZG16, KIF22, MAZ, PRRT2, MVP, CDIPT, SEZ6L2, ASPHD1, KCTD13, TMEM219, TAOK2, HIRIP3, INO80E, DOC2A, FAM57B, ALDOA, PPP4C, TBX6, YPEL3, GDPD3, MAPK3	+	+	Yes
13	TA	dup	8p11.1-p11.21	3	42,935,729	43,776,564	841	FNTA, SGK196, HGSNAT, POTEA	+	+	Yes
14	VSD, ASD, PA	del	10q25.1	1	110,420,129	111,116,531	696	RNU6-53, MAPKAPK5P1-001	-	+	Yes
19	VSD	dup	Yp11.2	2	9,664,007	9,997,425	333	TTTY23, TTTY23B	-	+	NP
20	ASD, PDA, PA	dup	2q13	3	110,504,318	111,365,996	862	RGPD5, RGPD6, LIMS3, LIMS3L, LIMS3-LOC440895, LOC440895, LOC100288570, LOC440894, MIR4267, MALL, MIR4436B2, MIR4436B1, NPHP1, LINC00116, LOC100507334, LOC151009	-	+	Yes
21	VSD	dup	7q21.13	3	88,819,024	89,678,695	860	ZNF804B	+	+	Yes
24	VSD, TA, PA	del	16p11.1-p11.2	1	34,197,616	35,158,405	961	UBE2MP1, LOC283914, LOC146481, LOC100130700, RN5S411, FLJ26245	-	-	Yes
26	BAV	del	17q12	1	34,477,385	36,283,612	1806	TBC1D3B, CCL3L3, CCL3L1, CCL4L2, CCL4L1, TBC1D3C, TBC1D3H, TBC1D3G, ZNHIT3, MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1, AATF, MIR2909, ACACA, C17orf78, TADA2A, DUSP14, SYNRG, DDX52, HNF1B, LOC284100	-	+	Yes
29	PDA	del	5p15.1-p15.33	1	113,576	17,511,896	17,398	PLEKHG4B, LRRC14B, CCDC127, SDHA, PDCD6, AHRR, C5orf55, EXOC3, PP7080, SLC9A3, MIR4456, CEP72, TPPP, ZDHHC11, BRD9, TRIP13, LOC100506688, NKD2, SLC12A7, MIR4635, SLC6A19, SLC6A18, TERT, MIR4457, CLPTM1L, SLC6A3, LPCAT1, SDHAP3, LOC728613, MIR4277, MRPL36, NDUFS6, IRX4, IRX2, C5orf38, LOC285577, IRX1, LOC340094, ADAMTS16, KIAA0947, FLJ33360, MED10, UBE2QL1, LOC255167, NSUN2, SRD5A1, PAPD7, MIR4278, MIR4454, LOC442132, ADCY2, C5orf49, FASTKD3, MTRR, LOC729506, LOC100505738, MIR4458, SEMA5A, MIR4636, LOC100505806, SNORD123, TAS2R1, LOC285692, FAM173B, CCT5, CMBL, MARCH6, ROPN1L, ANKRD33B, DAP, CTNND2, TAG, DNAH5, TRIO, FAM105A, FAM105B, ANKH, LOC100130744, MIR4637, FBXL7, MARCH11, ZNF622, FAM134B, MYO10, LOC285696, BASP1, LOC401177	-	+	NP
30	ASD	dup	5q33.2	3	154,330,014	154,664,212	334	MRPL22, KIF4B	-	-	NP
35	ToF, PA, PLSVC	dup	15q21.1	3	48,023,616	49,017,024	993	SEMA6D, SLC24A5, MYEF2, CTXN2, SLC12A1, DUT, FBN1	-	+	Yes
40	ToF, PA, ASD, PLSVC	dup	3q26.2	3	168,485,398	170,468,489	1983	EGFEM1P, MECOM, TERC, ACTRT3, MYNN, LRRC34, LRRIQ4, LRRC31, SAMD7, LOC100128164, SEC62, GPR160, PHC3, PRKCI, SKIL, CLDN11, SLC7A14	-	+	Yes
52	ToF, PA, ASD	dup	2p22.3	3	32,628,617	33,334,307	706	BIRC6, MIR558, TTC27, MIR4765, LINC00486, LOC100271832, LTBP1	+	+	Yes
58	ToF, PA	dup	6q14.3	3	87,387,316	87,921,049	534	HTR1E, CGA, ZNF292	-	+	Yes
59	ToF, PA, MVP	dup	16q23.1	3	77,923,068	78,596,237	673	VAT1L, CLEC3A, WWOX	-	+	Yes
63	ToF, PA	dup	3p26.3	3	1,750,535	2,205,306	455	CNTN4, CNTN4-AS2	+	+	Yes
67	ToF	dup	3p26.3	3	1,775,844	2,158,248	382	CNTN4, CNTN4-AS2	+	+	No
71	ToF	del	10q22.3-q23.2	1	81,446,577	89,253,430	7807	LOC650623, LOC642361, LOC100288974, MBL1P, SFTPD, LOC219347, C10orf57, PLAC9, ANXA11, LOC439990, MAT1A, DYDC1, DYDC2, FAM213A, TSPAN14, SH2D4B, NRG3, GHITM, C10orf99, CDHR1, LRIT2, LRIT1, RGR, LOC170425, FAM190B, GRID1-AS1, GRID1, MIR346, WAPAL, OPN4, LDB3, BMPR1A, MMRN2, SNCG, C10orf116, AGAP11, FAM25A, GLUD1, FAM35A, FAM22A, LOC728190, LOC439994, FAM22D, LOC728218	-	+	Yes
72	VSD, PA, ASD, TGA	dup	2p24.3-p25.3	3	12,770	14,851,012	14,838	FAM110C, SH3YL1, ACP1, FAM150B, TMEM18, LOC339822, SNTG2, TPO, PXDN, MYT1L, LOC730811, TSSC1, TRAPPC12, ADI1, RNASEH1, LOC100506054, RPS7, COLEC11, ALLC, LOC100505964, LOC727982, SOX11, LOC150622, LOC400940, LINC00487, CMPK2, RSAD2, LOC386597, RNF144A, LOC100506274, LOC339788, LINC00299, ID2, KIDINS220, MBOAT2, ASAP2, ITGB1BP1, CPSF3, IAH1, ADAM17, YWHAQ, TAF1B, GRHL1, KLF11, CYS1, RRM2, C2orf48, MIR4261, HPCAL1, ODC1, SNORA80B, NOL10, ATP6V1C2, PDIA6, KCNF1, FLJ33534, C2orf50, PQLC3, ROCK2, LINC00570, E2F6, GREB1, MIR4429, NTSR2, LPIN1, MIR4262, TRIB2, MIR3125, LOC100506474, FAM84A	-	+	Yes
		del	4q35.1-q35.2	1	186,464,011	190,957,473	4493	SORBS2, TLR3, FAM149A, FLJ38576, CYP4V2, KLKB1, F11, LOC285441, MTNR1A, FAT1, LOC339975, ZFP42, TRIML2, TRIML1, LOC401164, HSP90AA4P, FRG1, LOC100288255, FRG2	-	+	Yes
		del	16p12.2	1	21,576,802	21,951,415	375	METTL9, IGSF6, OTOA, RRN3P1	+	+	Yes
77	VSD, PA, ASD, PLSVC	del	8p23.1	1	8,093,065	11,935,465	3842	FLJ10661, SGK223, CLDN23, MFHAS1, ERI1, MIR4660, PPP1R3B, LOC157273, TNKS, MIR597, LINC00599, MIR124-1, MSRA, PRSS55, RP1L1, C8orf74, SOX7, PINX1, MIR1322, XKR6, MIR598, MTMR9, SLC35G5, TDH, C8orf12, FAM167A, BLK, LINC00208, GATA4, NEIL2, FDFT1, CTSB, DEFB136, DEFB135, DEFB134, LOC100133267, DEFB130	-	+	PV
78	BAV, EA, SV	del	22q13.33	1	50,100,435	51,197,838	1097	BRD1, LOC90834, ZBED4, ALG12, CRELD2, PIM3, IL17REL, MLC1, MOV10L1, PANX2, TRABD, SELO, TUBGCP6, HDAC10, MAPK12, MAPK11, PLXNB2, FAM116B, PPP6R2, SBF1, ADM2, MIOX, LMF2, NCAPH2, SCO2, TYMP, ODF3B, KLHDC7B, SYCE3, CPT1B, CHKB-CPT1B, CHKB, LOC100144603, MAPK8IP2, ARSA, SHANK3, ACR, RPL23AP82	-	+	PV

	Case 8	Case 26	Case 29	Case 40	Case 71	Case 72	Case 77	Case 78	22q11.2DS^a a McDonald-McGinn et al.2
Genomic imbalance	del 16p11.2	del 17q12	del 5p15.1-p15.33	dup 3q26.2	del 10q22.3-q23.2	del 4q35.1-q35.2	del 8p23.1	del 22q13.33	del 22q11.2
Size of aberration	611 kb	1.8 Mb	17.4 Mb	2.0 Mb	7.8 Mb	4.5 Mb	3.8 Mb	1.1 Mb	1.5-3.0 Mb
Gender	Male	Male	Male	Female	Male	Female	Female	Male	Evenly distributed
Age at evaluation	7 y	11 y	1 y	2 y	3 y	39 y	5 y	10 y	56% ≤5 y
Growth delay	+	-	+	-	-	-	-	-	NR
Congenital heart disease	+	+	+	+	+	+	+	+	74%
Palatal abnormalities	+	+	+	+	-	-	+	-	69%
Facial dysmorphisms	+	+	+	+	+	+	+	+	Common
Immunological abnormalities	+	-	-	-	+	-	+	+	Common
Developmental delay	-	+	+	-	+	+	+	+	70-90%
Feeding problems	-	-	-	-	-	-	-	+	30%
Hearing loss	+	+	-	-	-	-	-	-	39%
Eye abnormalities	-	-	-	-	-	-	-	-	≥69%
Neurological abnormalities	-	-	-	-	-	-	-	-	NR
Urinary tract anomalies	-	-	+	-	-	-	-	-	37%
Gastrointestinal anomalies	+	-	+	-	-	-	+	-	NR
Skeletal abnormalities	-	-	-	+	+	+	+	+	NR

Gene	OMIM	Functions	Process
IRX4	606199	Sequence-specific DNA binding	Establishment of organ orientation; heart development; regulation of transcription; DNA-templated
BMPR1A	601299	BMP receptor, RNA polymerase II transcription factor, protein homodimerization and protein serine/threonine kinase activity; ATP, sequence-specific DNA, SMAD, glycoprotein, metal ion and protein binding	BMP signaling pathway; cardiac conduction system development; cardiac right ventricle, dorsal aorta and mitral valve morphogenesis; heart formation
SORBS2	616349	Cytoskeletal adaptor activity; metal ion, poly(A) RNA and protein binding; structural constituent of cytoskeleton; structural constituent of muscle	Actin filament organization; biological process; cell adhesion; cell growth involved in cardiac muscle cell development; cell migration
ID2	600386	ATP, Rho GTPase, metal ion, poly(A) RNA and protein binding; protein dimerization activity	Membranous septum morphogenesis; metanephros development; multicellular organism development; natural killer cell differentiation
ROCK2	604002	Rho-dependent protein serine/threonine kinase, protein serine/threonine kinase and structural molecule activity	Centrosome duplication; cortical actin cytoskeleton organization; cytokinesis; ephrin receptor signaling pathway; negative regulation of angiogenesis
E2F6	602944	DNA, protein and transcription factor activity, sequence-specific DNA binding; transcription corepressor activity	Negative regulation of transcription from RNA polymerase II promoter; regulation of transcription involved in G1/S transition of mitotic cell cycle; transcription, DNA-templated
GATA4	600576	DNA, NFAT protein, RNA polymerase II transcription factor, activating transcription factor, chromatin, co-SMAD, enhancer sequence-specific DNA and sequence-specific DNA binding; transcription coactivator activity; zinc ion binding	Anatomical structure formation involved in morphogenesis; atrial septum, cardiac ventricle morphogenesis; blood coagulation; cell development; cell growth involved in cardiac muscle cell development; embryonic heart tube anterior/posterior pattern specification; endocardial cushion development; heart looping
SOX7	612202	Protein, transcription factor activity, sequence-specific DNA and transcription regulatory region DNA binding	Endoderm formation; negative regulation of cell proliferation; negative regulation of transcription, DNA-templated; positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; regulation of canonical Wnt signaling pathway; transcription, DNA-templated

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[1] * Corresponding author. E-mail:vlopes@fcm.unicamp.br (V.L. Gil-da-Silva-Lopes).