Chromosomal abnormalities and copy number variations in fetal left-sided congenital heart defects

SUMMARY OBJECTIVE: This study was to assess the genetic association of copy number variations in two genes (PRKAB2 and PPM1K) located in two regions (tetralogy of Fallot and ventricular septal defect) in a Chinese Han population. METHODS: A total of 200 congenital heart disease patients (100 tetralogy of Fallot patients and 100 ventricular septal defect patients) and 100 congenital heart defect-free controls were recruited, and quantitative real-time PCR analysis was used to replicate the association of two copy number variations with congenital heart defects in a Chinese Han population. RESULTS: One deletion at PRKAB2 and one duplication at PPM1K were found in two of the tetralogy of Fallot patients, respectively; while all these regions were duplicated in both ventricular septal defect patients and in the 100 congenital heart defects-free controls. CONCLUSIONS: We replicated the copy number variations at the disease-candidate genes of PRKAB2 and PPM1K with tetralogy of Fallot in a Chinese Han population, and in patients with ventricular septal defect mutations in these two genes were not found. These results indicate the same molecular population genetics exist in these two genes with different ethnicity. This shows that these two genes are possibly specific pf tetralogy of Fallot candidates.

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Multiplex Ligation-Dependent Probe Amplification Analysis ofGATA4Gene Copy Number Variations in Patients with Isolated Congenital Heart Disease

Disease Markers ◽

10.1155/2010/530360 ◽

2010 ◽

Vol 28 (5) ◽

pp. 287-292 ◽

Cited By ~ 7

Author(s):

Valentina Guida ◽

Francesca Lepri ◽

Raymon Vijzelaar ◽

Andrea De Zorzi ◽

Paolo Versacci ◽

...

Keyword(s):

Congenital Heart Defects ◽

Copy Number ◽

High Performance ◽

Congenital Heart ◽

Clinical Symptoms ◽

Heart Defects ◽

Gene Mutations ◽

Copy Number Variations ◽

Deletion Syndrome ◽

Dependent Probe

GATA4mutations are found in patients with different isolated congenital heart defects (CHDs), mostly cardiac septal defects and tetralogy of Fallot. In addition,GATA4is supposed to be the responsible gene for the CHDs in the chromosomal 8p23 deletion syndrome, which is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. Thus far, no study has been carried out to investigate the role ofGATA4copy number variations (CNVs) in non-syndromic CHDs. To explore the possible occurrence ofGATA4gene CNVs in isolated CHDs, we analyzed by multiplex ligation-dependent probe amplification (MLPA) a cohort of 161 non-syndromic patients with cardiac anomalies previously associated withGATA4gene mutations. The patients were mutation-negative forGATA4,NKX2.5, andFOG2genes after screening with denaturing high performance liquid chromatography. MLPA analysis revealed that normalized MLPA signals were all found within the normal range values for all exons in all patients, excluding a major contribution ofGATA4gene CNVs in CHD pathogenesis.

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Estimate the Frequency of Causal Genetic Variants in Fetuses With Congenital Heart Defects: a Chinese Cohort Study

10.21203/rs.3.rs-698990/v1 ◽

2021 ◽

Author(s):

Fengying Lu ◽

Peng Xue ◽

Bin Zhang ◽

Jing Wang ◽

Jianbin Liu ◽

...

Keyword(s):

Cohort Study ◽

Congenital Heart Defects ◽

Congenital Heart ◽

Chromosomal Abnormalities ◽

Diagnostic Yield ◽

Hot Spot ◽

Isolated Heart ◽

Heart Defects ◽

Copy Number Variations ◽

Considerable Proportion

Abstract Purpose: This cohort study was designed to assess the prevalence of chromosomal abnormalities in fetuses with different types of congenital heart defects (CHD).Methods: In a cohort of 200 fetuses with CHD, we performed prenatal chromosome microarray analysis (CMA) firstly, and then WES analysis was carried out on some fetuses with negative CMA results. Meanwhile, we conducted a systematic literature search on hot spot pathogenic copy number variations (CNVs) related to CHD in the Chinese population.Results: Chromosomal abnormalities were detected in 49 (24.5%) fetuses after prenatal CMA detection, including 23(11.5%) with aneuploidies and 26 (13.0%) with significant clinical CNVs. The additional diagnostic yield diagnosed by followed WES was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD combined with extracardial structural abnormalities or soft markers. The chromosome abnormal rate of complex CHD group was higher than that of the simple CHD group, but the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNVs detected in CHD fetuses was the 22q11.2 deletions, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, duplications of 17q12.Conclusion: CMA is the recommended initial examination for cases of CHD in the prenatal setting, whether it is simple heart defects or isolated heart defect. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.

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Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02167-8 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Fengying Lu ◽

Peng Xue ◽

Bin Zhang ◽

Jing Wang ◽

Bin Yu ◽

...

Keyword(s):

Cohort Study ◽

Congenital Heart Defects ◽

Chromosomal Abnormality ◽

Congenital Heart ◽

Chromosomal Abnormalities ◽

Diagnostic Yield ◽

Isolated Heart ◽

Heart Defects ◽

Copy Number Variations ◽

Considerable Proportion

Abstract Background The belief that genetics plays a major role in the pathogenesis of congenital heart defects (CHD) has grown popular among clinicians. Although some studies have focused on the genetic testing of foetuses with CHD in China, the genotype–phenotype relationship has not yet been fully established, and hotspot copy number variations (CNVs) related to CHD in the Chinese population are still unclear. This cohort study aimed to assess the prevalence of chromosomal abnormalities in Chinese foetuses with different types of CHD. Results In a cohort of 200 foetuses, chromosomal abnormalities were detected in 49 (24.5%) after a prenatal chromosome microarray analysis (CMA), including 23 foetuses (11.5%) with aneuploidies and 26 (13.0%) with clinically significant CNVs. The additional diagnostic yield following whole exome sequencing (WES) was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers. The chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group; however, the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNV detected in CHD foetuses was the 22q11.2 deletion, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, and duplications of 17q12. Conclusions CMA is the recommended initial examination for cases of CHD in prenatal settings, for both simple heart defects and isolated heart defects. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.

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