DOI: 10.1002/pd.4383

ORIGINAL ARTICLE

Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array Can Liao*, Ru Li, Fang Fu, Guie Xie, Yongling Zhang, Min Pan, Jian Li and Dongzhi Li Department of Prenatal Diagnostic Center Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China *Correspondence to: Can Liao. E-mail: [email protected]

ABSTRACT Objective This study aimed to detect genomic imbalances in fetuses with congenital heart defect (CHD) by high-resolution single-nucleotide polymorphism (SNP) array. Methods A total of 99 fetuses with CHDs with or without other ultrasound anomalies (including structural anomalies and soft markers) but normal karyotypes were investigated using Affymetrix CytoScan HD array. Results Clinical significant copy number variations (CNVs) were detected in 19 fetuses (19.2%). The proportion for variants of unknown significance was 3% after parental analysis. Five known microdeletion/microduplication syndromes were identified. The detection rate in CHD plus structural anomaly (27.8%) or soft marker (25%) group was higher than but not statistically different from isolated CHD group (15.9%). There was no significant difference between the detection rates in simple and complex CHD groups (20.7% vs. 16.7%). The detection rate in fetuses with CHD and neurologic defect was significantly higher than those with other types of structural anomaly (75% vs. 14.3%, P < 0.05). Conclusions Our results demonstrated the value of high-resolution SNP arrays in prenatal diagnosis of CHD; it should become an integral aspect in clinically molecular diagnosis and genetic counseling. The complexity of the cardiac defect was not related to the frequency of clinical significant CNV, but the presence of neurologic defect was related. © 2014 John Wiley & Sons, Ltd.

Funding sources: This study was funded by Guangzhou Health Bureau Key Project (201102A212026), National Natural Science Foundation of China (81100435), Guangzhou Science and Technology Bureau Project (201300000086) and Guangdong Provincial Medical Research Foundation (A2013515). Conflicts of interest: None declared

INTRODUCTION Chromosome microarray analysis (CMA) is increasingly used in clinical genetics both in postnatal and prenatal settings. This method is recommended by the International Standard Cytogenomic Array Consortium as the first-line cytogenetic diagnostic test in disorders such as developmental delay, intellectual disability, autism and multiple congenital anomalies.1 It is also a valuable tool to detect chromosome aberrations in prenatal diagnosis, particularly in fetuses with abnormal ultrasound findings and normal karyotypes.2 Congenital heart defect (CHD) is the most common congenital abnormality affecting 0.8% of live births, and the causes of most cases are unknown.3 In the past few years, our understanding of molecular pathways in cardiac development has grown greatly. Chromosomal aberrations, single gene defects, maternal age, disease, radiation, microbial infection and chemical agents are all potentially etiologic in the pathogenesis of CHD.4,5 About 20% of CHD is attributable to Mendelian diseases or chromosomal aneuploidies; however, the remaining 80% CHD is attributable to non-Mendelian causes that are poorly understood.6 Recently, CMA has been Prenatal Diagnosis 2014, 34, 858–863

successfully applied to identify copy number variations (CNVs) in postnatal and prenatal subjects with CHD, and has led to increase the identified contribution of chromosomal abnormalities.7–18 Here, we present the results of genome-wide high-resolution single-nucleotide polymorphism (SNP) array analysis in 99 fetuses with CHDs with or without other ultrasound anomalies (including structural anomalies and soft markers) but normal karyotype, and evaluate its clinical value in prenatal diagnosis of CHD.

METHODS Subjects Between December 2010 and September 2013, 7658 pregnant women were referred to Prenatal Diagnostic Center in Guangzhou Women and Children’s Medical Center for karyotyping on chorionic villus (n = 525), amniotic fluid (n = 6034) and cord blood (n = 1099) samples. In 176 of them, the fetuses presented CHDs with or without other ultrasound anomalies. Fetuses with abnormal or failed karyotypes were excluded from the study (n = 50). The remaining (n = 126) © 2014 John Wiley & Sons, Ltd.

Chromosome microarray analysis of CHD

revealed normal karyotype results. Fetuses with the following ultrasound findings (n = 27) were also excluded from the study: isolated persistent left superior vena cava or valve insufficiency, coronary anomaly or cardiac tumor. Finally, 99 fetuses (56.3%) were included in the array test, of which 69 were with isolated CHD, 30 were with CHD plus other ultrasound anomalies including structural anomalies (n = 18) and soft markers (n = 12, such as increased nuchal translucency ≥3.0 mm, nasal bone dysplasia, echogenic foci in the liver or bowel, single umbilical artery, persistent right umbilical vein). When combined with other forms of CHDs, the diagnosis of persistent left superior vena cava or valve insufficiency was ignored. CHDs were classified using a method described in detail by Botto et al.19 Simple CHD (n = 87) was defined as anatomically discrete or a single or dominant entity, and complex CHD (n = 6) as single ventricle, L-transposition of the great arteries or multiple heart anomaly (involved three or more defects). The types of CHD were summarized in Table 1. Fetal samples were collected using chorionic villus sampling (n = 1), amniocentesis (n = 9) and cord blood sampling (n = 89), according to the gestational weeks (ranged from 13+ weeks to 36+ weeks). Parental blood samples were collected for every fetal sample to exclude maternal contamination and to assist in interpreting the CNVs when necessary. This study was approved by the ethics committee at the Guangzhou Women and Children’s Medical Center, and informed consent were obtained from the prenatal couples for invasive prenatal diagnosis.

859

Table 1 The types of CHDs and frequencies for fetuses with clinical significant CNVs in the study CHD classification Conotruncal

Prenatal Diagnosis 2014, 34, 858–863

5

2

2

Double outlet right ventricle

2

0

Truncus arteriosus

4

1

Tetralogy of fallot

7

2

d-TGA

7

0

6

2

AVSD complete

4

1

AVSD transitional

1

1

AVSD unspecified

1

0

APVR

3

0

LVOTO

8

2

Aortic coarctation

5

1

Hypoplastic left heart syndrome

3

1

Pulmonary stenosis

14

2

8

2

Ebstein anomaly

3

0

Double chamber right ventricle

1

0

Tricuspid atresia

2

0

26

4

12

2

Septal VSD perimembranous VSD muscular

4

1

VSD not specified

9

0

VSD + ASD not specified Complex CHDa

1

1

6

1

Single ventricle

2

0

Single ventricle + truncus arteriosus

3

0

Single ventricle + TGA

1

1

6

0

3

0

Heterotaxy Heterotaxy: simple CHD Heterotaxy: complex CHD Other CHDs

3

0

8

3

Right aortic arch

2

1

Valve insufficiencyb

3

1

PLSVCc Total

RESULTS The CNVs were identified in 98 fetuses (99%), ranging in size from 100 kb to 5.6 Mb. Of the 98 fetuses, 95 (97%) had more than one CNV. CNVs identified in 67 fetuses were considered to be likely benign, listed in DGV or no known gene included. Twenty-one clinical significant CNVs were detected in 19 fetuses (19.2%), which overlapped with the known syndrome or with a DECIPHER entry or comprised genes contributing to CHD (Table 2). Fetuses 2 and 6 had two clinical significant

22

RVOTO

Genomic DNAs were extracted from chorionic villus, amniotic fluid, cord blood samples and peripheral blood using the Qiagen Mini Kits, according to the manufacturer’s protocol (Qiagen). Genome-wide high-resolution SNP array CytoScan HD (Affymetrix) was used containing both SNPs and oligonucleotide probes. Procedures for DNA digestion, ligation, PCR amplification, fragmentation, labeling and hybridization with the arrays were performed according to the manufacture’s protocols (Affymetrix). The reporting threshold of the copy number result was set at 100 kb with marker count ≥50. For the interpretation of the results, our in-house database and the following public databases were used: database of genomic variants (DGV, http://projects.tcag.ca/variation/), DECIPHER database (http://decipher.sanger.ac.uk/), Online Mendelian Inheritance in Man (http://www.omim.org), UCSC (http://genome.ucsc. edu/, hg19), the International Standards for Cytogenomic Arrays (https://www.iscaconsortium.org/) and CAG database (https:// www.cagdb.org). All CNVs were further confirmed by Real-Time Polymerase Chain Reaction.

Number of fetuses with significant CNVs

Interrupted aortic arch, type B

AVSD

Chromosome microarray analysis

Number of fetuses

3

1

99

19

CHD, congenital heart defect; CNVs, copy number variations; APVR, anomalous pulmonary venous return; ASD, atrial septal defect; AVSD, atrioventricular septal defect; LVOTO, left ventricular outflow tract obstruction; PLSVC, persistent left superior vena cava; RVOTO, right ventricular outflow tract obstruction; TGA, d-transposition of the great arteries; VSD, ventricular septal defect. Complex CHD, single ventricle, L-transposition of the great arteries or multiple heart anomaly (involved three or more defects). b All the fetuses with valve insufficiency were in association with ultrasound soft markers. c One fetus with PLSVC plus soft marker, the other two with PLSVC plus structural anomalies. a

© 2014 John Wiley & Sons, Ltd.

C. Liao et al.

860

Table 2 Clinical significant CNVs detected in our study Case no. ID

CNVs

Size (kb)

Fetus 1

Mosaic trisomy chromosome 9

Fetus 2

Dup 1p12 (120181760120485891)

304

Dup Xp22.31 (64589398135644)

1677

Fetus 3

Del 2q13 (110504318111365996)

862

Fetus 4

Del 22q11.21 (2073014321800471)

Fetus 5 Fetus 6

Cardiac defect Aortic coarctation/ right aortic arch

Extra cardiac abnormalities

Known syndrome/disease related to CHD (OMIM ID)

Inheritance

Alagille syndrome (610205)

Inherited from mother

Dandy–Walker malformation —

Right aortic arch

Inherited from father VSD



Joubert syndrome (609583)

Not inherited

1070

Pulmonary stenosis/ VSD



Digeorge syndrome (188400)

Not inherited

Del 18q11.2 (1936031519500192)

140

VSD/increased cardiothoracic ratio



Left ventricular noncompaction 7 (615092)

Not inherited

Dup 9q34.3 (137672673141020389)

3348

Del 17p13.2-p13.3 (525-5031375)

5031

200

Tetralogy of fallot

Not inherited



Osteopathia striata with cranial sclerosis (300373)

Inherited from mother

Mitral insufficiency/ tricuspid insufficiency/ hydropericardium



22q11 duplication syndrome (608363)

Inherited from mother

AVSD



Multiple sulfatase deficiency (272200)

Not inherited

Osteopathia striata with cranial sclerosis (300373)

Inherited from mother

Joubert syndrome (609583)

Not inherited

Dup Xq11.2 (6321197663411741)

Fetus 8

Dup 22q11.21 (1864885521800471)

Fetus 9

Dup 3p26.1 (4127815-4327836)

Fetus 10

Dup Xq11.2 (63395160-64450154)

1055

Fetus 11

Del 2q13 (110504318111365996)

862

Fetus 12

Dup Xp22.31 (6455149-8135644)

1680

Tricuspid insufficiency/ pulmonary stenosis/ increased cardiothoracic ratio

Fetus 13

Del 22q11.21 (1891684221800797)

2884

VSD/interruption of aortic arch

Fetus 14

Del 1p36.22-p36.33 (1397489-9245572)

7848

ASD/VSD/tricuspid insufficiency/ Gerbode defecta

Fetus 15

Del 22q11.21 (1902465621465659)

2441

Fetus 16

Del 22q11.21 (1864479021465659)

Fetus 17

200

Miller–Dieker syndrome (247200) VSD

Fetus 7

3152

Not inherited

Agenesis of corpus callosum/ cerebellar hypoplasia/ increased echogenicity of renal parenchyma

Left ventricle dysplasia

Spina bifida



Single ventricle/ TGA

Persistent right umbilical vein —

Inherited from mother Digeorge syndrome (188400)

Inherited from mother

Nasal bone dysplasia

1p36 microdeletion syndrome

Not inherited

Tetralogy of fallot

Increased nuchal translucency

Digeorge syndrome (188400)

Not inherited

2821

AVSD/PLSVC

Double strephenopodia

Digeorge syndrome (188400)

Not inherited

Del 22q11.21 (1891684221465659)

2549

VSD/persistent truncus arteriosus/PLSVC



Digeorge syndrome (188400)

Not inherited

Fetus 18

Dup 22q13.2 (4146272941588927)

127

VSD/interruption of aortic arch/tricuspid insufficiency



Rubinstein–Taybi syndrome (613684)

Not inherited

Fetus 19

Del 17q12 (3447747936404104)

Renal cyst and diabetes syndrome (137920)

Not inherited

1927

PLSVC

Renal cyst

CNVs, copy number variations; CHD, congenital heart defect; OMIM, Online Mendelian Inheritance in Man; ASD, atrial septal defect; AVSD, atrioventricular septum defect; PLSVC, persistent left superior vena cava; TGA, transposition of the great arteries; VSD, ventricular septal defect. a Gerbode defect means left ventricular right atrium communication.

Prenatal Diagnosis 2014, 34, 858–863

© 2014 John Wiley & Sons, Ltd.

Chromosome microarray analysis of CHD

861

CNVs, respectively. Parental analysis showed that CNVs in six fetuses were inherited from parents with no reported congenital anomaly. In nine fetuses, we detected known microdeletion and microduplication syndromes: 22q11.2 deletion syndrome (n = 5), 22q11.2 duplication syndrome (n = 1), 1p36 microdeletion syndrome (n = 1), Miller–Dieker syndrome (n = 1), Renal cyst and diabetes syndrome (n = 1). After excluding the six fetuses with 22q11.2 deletion/ duplication syndrome, the detection rate was 14%. Of the 19 fetuses with clinical significant CNVs, 11 had isolated CHD and 8 had CHD plus other ultrasound anomalies (CHD plus structural anomalies: n = 5, CHD plus soft marker: n = 3), 18 had simple CHD and 1 had complex CHD. Detection rates in different groups were listed in Table 3. Fetuses with CHD plus other ultrasound anomalies had a higher detection rate than those with isolated CHD (26.9% vs. 15.9%), but no significant difference existed (Fisher exact test, P > 0.05). Likewise, the detection rate in CHD plus structural anomaly (27.8%) or soft marker (25%) group was higher than but not statistically different from isolated CHD group (15.9%). Similarly, there was no difference between the detection rates in CHD plus structural anomaly and soft marker groups (27.8% vs. 25%), as well as in simple and complex CHD groups (20.7% vs. 16.7%). The presence of neurologic defect in association with CHD (n = 3/4, 75%) resulted in a greater probability of microdeletion or microduplication when compared with other types of structural anomalies (n = 2/14, 14.3%) (Fisher exact test, P < 0.05). In addition, simple and isolated CHD had a detection rate of 16.9% (10/59). The detection rate in the following cardiac defects in isolation or with additional ultrasound anomalies were in turn atrioventricular septal defect (n = 2/6, 33.3%), left heart defect (n = 2/8, 25%), conotruncal defect (n = 5/ 22, 22.7%), septal defect (n = 4/26, 15.4%) and right heart defect (n = 2/14, 14.3%). No clinical significant CNV was detected in fetuses with anomalous pulmonary venous return or heterotaxy. In addition, CMA revealed a mosaic trisomy of chromosome 9 in fetus 1. The clinical significance of CNVs identified in 13 fetuses could not be determined, and were initially categorized as variants of unknown significance (VOUS). Following parental analysis revealed that CNVs in 10 of the 13 fetuses were inherited from normal parents. CNVs in the other three fetuses were not inherited and the significance remained unclear: 8q24 duplication (324 kb, 143515771-143839318), 2q33 duplication (226 kb, 203263070203488804) and 16p12 deletion (369 kb, 21576802-21946045). Thus, the VOUS proportion was 3% (3/99) in our study.

Table 3 Detection rates for clinical significant copy number variations in congenital heart defect (CHD) groups Group Isolated CHD CHD plus other ultrasound anomalies

Detection rate (%) 11/69 (15.9) 8/30 (26.9)

CHD plus structural anomalies

5/18 (27.8)

CHD plus soft marker

3/12 (25.0)

Simple CHD Complex CHD Simple and isolated CHD

Prenatal Diagnosis 2014, 34, 858–863

18/87 (20.7) 1/6 (16.7) 10/59 (16.9)

DISCUSSION The widespread use of CMA has implicated CNVs in many disorders. In the past few years, a number of studies have established the relevance of CNVs in the etiology of CHD.7–18 In postnatal analysis, CMA has already been extensively used to investigate chromosome aberrations in CHD. Thienpont et al. reported study in 60 patients with CHD plus extra cardiac abnormalities using customized 1-Mb Bacterial Artificial Chromosome (BAC) array; the detection rate of pathogenic CNVs was 17%, and the rate of VOUS was 11.7%.7 Goldmuntz et al. reported submicroscopic rearrangements in 20.7% of 58 patients with cardiac and other congenital anomalies using Affymetrix GeneChip 100 K array, and the VOUS rate was 3.4%.11 Syrmou et al. scanned 55 patients with CHD and at least one additional indication of chromosomal abnormality using Agilent 244 K or 4 × 180 K oligo arrays; CNVs were detected in 52.7% patients containing genes associated with heart disease.13 Erdogan et al. studied 105 patients with isolated CHD using 1-Mb BAC array, and the diagnostic rate was 17.1%.9 They declared that screening patients with CHD by microarray was instrumental to reveal the syndromic nature of disease before additional symptoms manifest. However, Richards did not advocate routinely screening patients with isolated CHD by microarray.8 The authors reported in their study that 25% of CHDs with additional birth defects had abnormal microarray results, whereas no submicroscopic imbalance was detected in patients with isolated heart defect. Similar findings were reported by Breckpot; they concluded that the frequency of causal CNVs in non-syndromic CHD is much lower than in syndromic cases (3.6% vs. 19%, respectively).10 Recently, Soemedi and Lalani established the contribution of rare CNVs to CHD.14,15 Just in the past 2 years, few studies have been published specifically evaluating the usefulness of CMA in prenatal diagnosis of fetuses with CHD. Schmid et al. performed CMA in 12 fetuses with CHD, normal karyotype and negative for 22q11.2 deletion syndrome; the detection rate for causal CNVs was 25%.16 Mademont et al. reported that the diagnostic yield could be increased by 2% (1/51) in fetuses with CHD (negative for 22q11.2 deletion) if CMA was used as a complementary tool to conventional cytogenetics.17 Yan et al. reported study in 76 fetuses with CHD, normal karyotype and negative for 22q11.2 deletion; the detection rate for pathogenic CNVs was 6.6%, and the VOUS rate was 5.3%.18 In the present study, 99 fetuses with CHD and normal karyotypes were screened by genome-wide high-resolution SNP array. The overall detection rate for clinical significant CNVs was 19.2% (14% after excluding 22q11.2 deletion/ duplication), and the VOUS proportion was 3%. Compared with the previous reports either in syndromic or non-syndromic CHD subjects,7–18 the detection rate was relatively high, but the VOUS rate did not increase obviously in the study. Our results demonstrated that denser arrays with high-resolution will lead to a proportional increase in number of clinically significant CNVs10; parental analysis should be included to assist in interpreting CNVs with unknown significance. Soft markers are usually used to identify fetus at risk for aneuploidy; in this study, clinical significant CNVs were © 2014 John Wiley & Sons, Ltd.

C. Liao et al.

862

identified in 25% of the fetuses with CHD plus soft marker, and the detection rate was higher than (not statistically different from) those with isolated CHD (25% vs. 15.9%). Our results illustrated that soft marker is also an important notice for submicroscopic chromosome aberrations in fetus with ultrasound findings. We observed that no significant difference existed between the detection rates in simple and complex CHD groups, which indicated that the complexity of the cardiac defect was not related to the frequency of clinical significant CNV. Our results showed that fetuses with CHD plus neurologic defect had a higher incidence of microdeletion/microduplication compared with CHD plus other types of congenital anomalies (75% vs. 14.3%, P < 0.05); this phenomenon was also observed by Richards.8 Similar with reports from Richards and Breckpot,8,10 the detection rate in multiple malformation (CHD with additional structural anomalies) group was higher than (but not statistically different from) isolated CHD group (27.8% vs. 15.9%), which demonstrated that the more malformations involved, the more possibility to detect pathogenic CNVs. By using genome-wide high-resolution SNP array, we still obtained high detection rate in fetuses with isolated CHD (15.9%). In general, we approve routinely screening fetuses with CHD by CMA, to reveal the syndromic nature of disease and to uncover additional disease association CNVs. In clinical setting, the crucial issue is to select a suitable array able to detect the majority of pathological CNVs but without detecting too many VOUS; parental analysis should be included when necessary. Our results showed high detection rate in cases with atrioventricular septal defect (33.3%), left heart defect (25%, including hypoplastic left heart = 33.3%) and conotruncal defect (22.7%) in isolation or with additional anomalies. Although the subgroup sample size is small in our study cohort, similar results were obtained in the previously published data.17,20,21 Shaffer et al. reported the highest detection rate for submicroscopic aberration in fetuses with hypoplastic left heart (16.2%).20 Study from Hartman et al. showed that the most common chromosomal abnormalities were observed in infants with interrupted aortic arch (69.2%) and atrioventricular septal defect (67.2%).21 Mademont reported the highest detection rate of chromosomal abnormality in fetuses with left heart defect (29.6%).17 These data indicate that atrioventricular septal defect and left heart defect are most likely to be associated with chromosomal imbalances, especially for hypoplastic left heart. We did not identify microdeletion or microduplication in anomalous pulmonary venous return or heterotaxy, the possible reason is that our sample size is not large enough. However, study from Hartman also showed the least detection rate in heterotaxy (n = 2/91, 2.2%), which suggest such defect is poorly associated with chromosomal abnormalities.21 Well-described microdeletion or microduplication syndromes were identified in nine fetuses. The most common findings were 22q11.2 deletion syndrome identified in five fetuses (5.1%). The frequency is consistent with previously published data (6.4%).17 Recent study has reported that CNVs at 1q21.1 and deletions at 15q11.2 were strongly associated with the risk of sporadic, non-syndromic CHD.14 We did not identify these CNVs, although the clinical phenotype of the Prenatal Diagnosis 2014, 34, 858–863

most cases in our cohort was isolated CHD (n = 69/99, 69.7%). In 77 of the 99 fetuses (77.8%), no etiological diagnosis could be reached. Multifactorial etiologies will probably explain a large part of the remaining cases. Microarrays with SNPs and oligonucleotide probes not only provide copy number information but also identify mosaic. In our study, CMA revealed a mosaic trisomy of chromosome 9. Fetus 1 showed aortic coarctation, right aortic arch and Dandy–Walker malformation on ultrasound, conventional karyotype for the cord blood sample at 26+ weeks indicated normal result. The microarray test revealed a mosaic trisomy of chromosome 9 with 75% percentage. We further rechecked the karyotype and found the mosaic with ratio of 6%: 47, XY, + 9[3]/ 46,XY[47]. The possible reason for the misdiagnosis and the great discordance in mosaic ratio may be unsatisfactory cell culture and limited karyotypes obtained. The CNVs detected in six fetuses were inherited from reportedly unaffected parents. Nonetheless, these inherited CNVs still hold clinical relevance. Firstly, the parents are just seemingly healthy and have not taken thorough physical examination for mild syndromic features. Secondly, it may be due to complex mechanisms such as incomplete penetrance, the effect of imprinted genes or modifier, mutation in recessive gene and position effect.22–24

CONCLUSION In summary, our study illustrates that CMA is a valuable tool to identify microdeletion and microduplication in prenatal diagnosis of CHD. By using genome-wide high-resolution SNP array, we could obtain high diagnostic rate and uncover additional disease association CNVs including mosaic. Parental analysis should be included to assist in interpreting the CNVs with unknown significance. The complexity of the cardiac defect was not related to the frequency of clinical significant CNV, whereas the presence of neurologic defect in association with CHD resulted in a greater probability of microdeletion or microduplication compared with other types of structural anomalies. With more wide application of CMA in genetic disorders, increasing accumulation of data on CNVs will decrease the VOUS remarkably. CMA should become an integral aspect in clinically molecular diagnosis and genetic counseling. Submicroscopic deletions and duplications identified in the present study will advance the molecular understanding of etiology in CHD. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Recent studies have established the relevance of CNVs in the etiology of CHD.

WHAT DOES THIS STUDY ADD? • This study demonstrated the value of genome-wide high-resolution SNP arrays in prenatal diagnosis of congenital heart defect and give a high detection rate of clinical significant genomic imbalance, especially for detecting mosaic. Submicroscopic deletions/ duplications identified in this study will advance the molecular understanding of etiology in congenital heart defect.

© 2014 John Wiley & Sons, Ltd.

Chromosome microarray analysis of CHD

863

REFERENCES 1. Coppinger J, Alliman S, Lamb AN, et al. Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray. Prenat Diagn 2009;29:1156–66. 2. American College of Obstetrics and Gynecology. ACOG Committee Opinion No. 446: array comparative genomic hybridization in prenatal diagnosis. Obstet Gynecol 2009;114:1161–3. 3. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900. 4. Tennstedt C, Chaoui R, Korner H, Dietel M. Spectrum of congenital heart defects and extracardiac malformations associated with chromosomal abnormalities: results of a seven year necropsy study. Heart 1999;82:34–9. 5. Hameed AB, Sklansky MS. Pregnancy: maternal and fetal heart disease. Curr Probl Cardiol 2007;32:419–94. 6. Bentham J, Bhattacharya S. Genetic mechanisms controlling cardiovascular development. Ann N Y Acad Sci 2008;1123:10–9. 7. Thienpont B, Mertens L, de Ravel T, et al. Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur Heart J 2007;8:2778–84. 8. Richards AA, Santos LJ, Nichols HA, et al. Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr Res 2008;64:358–63. 9. Erdogan F, Larsen LA, Zhang L, et al. High frequency of submicroscopic genomic aberrations detected by tiling path array comparative genome hybridisation in patients with isolated congenital heart disease. J Med Genet 2008;45:704–9. 10. Breckpot J, Thienpont B, Peeters H, et al. Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects. J Pediatr 2010;156:810–7. 11. Goldmuntz E, Paluru P, Glessner J, et al. Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies. Congenit Heart Dis 2011;6:592–602. 12. Tomita-Mitchell A, Mahnke DK, Struble CA, et al. Human gene copy number spectra analysis in congenital heart malformations. Physiol Genomics 2012;44:518–41. 13. Syrmou A, Tzetis M, Fryssira H, et al. Array comparative genomic hybridization as a clinical diagnostic tool in syndromic and nonsyndromic congenital heart disease. Pediatr Res 2013;73:772–6.

Prenatal Diagnosis 2014, 34, 858–863

14. Soemedi R, Wilson IJ, Bentham J, et al. Contribution of global rare copynumber variants to the risk of sporadic congenital heart disease. Am J Hum Genet 2012;91:489–501. 15. Lalani SR, Shaw C, Wang X, et al. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur J Hum Genet 2013;21:173–81. 16. Schmid M, Stary S, Blaicher W, et al. Prenatal genetic diagnosis using microarray analysis in fetuses with congenital heart defects. Prenat Diagn 2012;32:376–82. 17. Mademont-Soler I, Morales C, Soler A, et al. Prenatal diagnosis of chromosomal abnormalities in fetuses with abnormal cardiac ultrasound findings: evaluation of chromosomal microarray-based analysis. Ultrasound Obstet Gynecol 2013;41:375–82. 18. Yan Y, Wu Q, Zhang L, et al. Detection of submicroscopic chromosomal aberrations by array-based comparative genomic hybridization in fetuses with congenital heart disease. Ultrasound Obstet Gynecol 2014;43:404–12. 19. Botto LD, Lin AE, Riehle-Colarusso T, et al. Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A Clin Mol Teratol 2007;79:714–27. 20. Shaffer LG, Rosenfeld JA, Dabell MP, et al. Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound. Prenat Diagn 21.

22.

23.

24.

2012;32:986–95. Hartman RJ, Rasmussen SA, Botto LD, et al. The contribution of chromosomal abnormalities to congenital heart defects: a populationbased study. Pediatr Cardiol 2011;32:1147–57. Feuk L, Marshall CR, Wintle RF, et al. Structural variants: changing the landscape of chromosomes and design of disease studies. Hum Mol Genet. 2006;15:R57–66. Rosenberg C, Knijnenburg J, Bakker E, et al. Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. J Med Genet 2006;43:180–6. Bisgaard AM, Kirchhoff M, Nielsen JE, et al. Transmitted cytogenetic abnormalities in patients with mental retardation: pathogenic or normal variants? Eur J Med Genet 2007;50:243–55.

© 2014 John Wiley & Sons, Ltd.

Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array.

This study aimed to detect genomic imbalances in fetuses with congenital heart defect (CHD) by high-resolution single-nucleotide polymorphism (SNP) ar...
95KB Sizes 0 Downloads 3 Views