Detection of copy number variants using chromosomal microarray analysis for the prenatal diagnosis of congenital heart defects with normal karyotype

Song, Tingting; Wan, Shanning; Liu, Yu; Xü, Ying; Dang, Yinghui; Zheng, Yijing; Li, Chunyan; Zheng, Jin; Chen, Biliang; Zhang, Jianfang

doi:10.1002/jcla.22630

Cited by 21 publications

(20 citation statements)

References 41 publications

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“…The estimated prevalence of pathogenic CNVs in 7.6% of our entire cohort corresponds to three previously described cohorts of fetuses with CHDs, as these report pathogenic CNVs in 8-11%. [22][23][24] The proportion of CNVs appeared slightly lower in postnatal cohorts that reported CNVs in 5-8% of neonates with CHDs. 25,26 One recent fetal cohort reported a prevalence of 16% pathogenic CNVs.…”

Section: Discussionmentioning

confidence: 96%

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects

Nisselrooij

Lugthart

Clur

et al. 2020

Genetics in Medicine

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Purpose: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling. Methods: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre-and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs. Results: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis. Conclusion: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.

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Section: Discussionmentioning

confidence: 96%

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects

Nisselrooij

Lugthart

Clur

et al. 2020

Genetics in Medicine

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“… 49 In this study, seven fetuses were detected with VOUS among 356 fetuses with CHD, with a 1.9% detection rate of VOUS, which was similar to previous studies. 34 , 39 , 50 Among the seven fetuses with CHD that were identified with VOUS, two were found to bear susceptibility loci for neurocognitive disorders, including a copy number loss of 1.4 Mb at the p13.11 region of the chromosome 16 and a copy number gain of 1.4 Mb at the q21.1-q21.2 region of the chromosome 1. Although pedigree analysis showed this mutation was inherited from the mother with a normal phenotype; however, the frequency of susceptibility loci for neurocognitive disorders is less than 1% in healthy populations.…”

Section: Discussionmentioning

confidence: 99%

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

Huang¹,

Cai²,

Wang³

et al. 2021

RMHP

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Objective This study aimed to examine the effectiveness of the SNP array for the prenatal diagnosis of congenital heart disease (CHD) screened by echocardiography. Patients and Methods A total of 356 pregnant women with fetal congenital heart malformations revealed by echocardiography at the Center for Prenatal Diagnosis of Fujian Maternal and Children Hospital during the period from November 2016 through July 2019 were recruited. The fetuses were assigned into three cohorts, including 142 with a single cardiac malformation, 106 with multiple cardiac malformations and 108 with cardiac and extracardiac malformations. All fetuses underwent chromosomal karyotyping and SNP array simultaneously, and the effectiveness of the SNP array for the prenatal diagnosis of CHD was evaluated. Results The overall prevalence of abnormal karyotypes was 9.3% among the 356 fetuses with CHD, and a higher proportion was found in fetuses with cardiac and extracardiac malformations (18.5%) than in those with single (5.6%) or multiple cardiac malformations (4.7%) ( P <0.05). Consistent with karyotype analysis, SNP array detected an additional 25 fetuses with pathogenic copy number variations (CNVs), seven with variant of unknown significance (VOUS) and seven with benign CNVs, and a lower proportion of abnormal CNV was found in fetuses with a single cardiac malformation (4.2%) than in those with multiple cardiac malformations (9.4%) or cardiac and extracardiac malformations (14.8%) ( P <0.05). Among the 33 fetuses with chromosomal abnormality, postnatal follow-up showed termination of pregnancy in 25 with pathogenic CNVs, one with VOUS, and six with normal karyotypes and SNP array findings but severe multiple malformations by ultrasonography. Conclusion SNP array increases the overall detection of abnormal CNVs by 9%, which improves the detection of CNVs associated with CHD. SNP array may serve as a tool for prenatal diagnosis of CHD that facilitates the discovery of pathogenic genes associated with CHD and provide valuable insights into the precision assessment of fetal prognosis during the prenatal counseling.

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“…Although CMA was widely applied in prenatal diagnosis for fetuses with structural malformations or ultrasonographic soft markers such as congenital heart defects, renal abnormalities, CNS abnormalities, increased nuchal translucency and so on, 7,9‐11 there are not enough studies especially for fetuses with CNS abnormalities illuminate the relationship between CNVs and the abnormalities detected by prenatal ultrasound. In previous study, Lijuan Sun et al 7 showed that the detected rate of pathogenic CNVs in 46 fetuses with CNS was 10.9%.…”

Section: Discussionmentioning

confidence: 99%

Detection of submicroscopic chromosomal aberrations by chromosomal microarray analysis for the prenatal diagnosis of central nervous system abnormalities

Song

Xü

et al. 2020

Clinical Laboratory Analysis

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Background Central nervous system (CNS) abnormalities are a group of serious birth defects associated with high rates of stillbirths, infant death, or abnormal development, and various disease‐causing copy number variations play a much more important role in the etiology of CNS abnormalities. This study intends to present a retrospective study of the prenatal diagnosis and the pregnancy outcome of fetuses diagnosed with CNS abnormalities, and evaluate the clinical value of chromosomal microarray analysis (CMA) in prenatal diagnosis of CNS abnormalities. Methods A total of 356 fetuses with CNS abnormalities with or without other ultrasound abnormalities subjected to invasive prenatal diagnosis at the first affiliated hospital of Air Force Medical University from January 2015 to August 2018. All cases have performed both karyotyping and CMA concurrently, but 20 fetuses with chromosome aneuploidy were excluded in the current study. Results The CMA identified pathogenic copy number variants (pCNVs) in 27/336 (8.03%) fetuses, likely pCNVs in 8/336 (2.38%) fetuses, and variants of unknown significance (VOUS) in 11/336 (3.27%) fetuses. A total of 222 cases had single CNS abnormalities and the pCNVs detection rate was 5.86% (13/222), the remaining 114 cases including CNS abnormalities plus other structural abnormalities, ultrasonographic soft markers and two or more CNS abnormalities, the pCNVs detection rate was 12.3% (14/114). Conclusions Fetuses with CNS abnormalities have a higher risk of chromosomal abnormalities, our study showed that CNVs play an important role in the etiology of CNS abnormalities. The application of CMA could increase the detection rate of pCNVs causing CNS abnormalities.

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Detection of copy number variants using chromosomal microarray analysis for the prenatal diagnosis of congenital heart defects with normal karyotype

Cited by 21 publications

References 41 publications

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects

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

Detection of submicroscopic chromosomal aberrations by chromosomal microarray analysis for the prenatal diagnosis of central nervous system abnormalities

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