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

2010 ◽  
Vol 28 (5) ◽  
pp. 287-292 ◽  
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.

scholarly journals Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population

2021 ◽  
Vol 7 ◽  
Author(s):  
Hairui Sun ◽  
Xiaoyan Hao ◽  
Xin Wang ◽  
Xiaoxue Zhou ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Gene Mutations ◽  
Copy Number Variant ◽  
Sequencing Analysis ◽  
Noncompaction Cardiomyopathy ◽  
Pathogenic Variants ◽  
Clinical Awareness

Objectives: Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM.Methods: We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigated for gestational age at diagnosis, gender, left or biventricular involvement, associated cardiac phenotypes, outcomes, and genetic testing data.Results: We identified 37 fetuses with NCCM out of 49,898 fetuses, indicating that the incidence of NCCM in the fetal population was 0.07%. Of the 37 fetuses, 26 were male, ten were female and one was of unknown gender. NCCM involvement biventricle is the most common (n = 16, 43%), followed by confined to the left ventricle (n = 14, 38%). Nineteen (51%) had additional congenital heart defects, with right-sided lesions being the most common (n = 14, 74%), followed by ventricular septal defects (n = 10, 53%). Hydrops fetalis was present in 12 cases (32%), of which four were atypical (pericardial effusion only). Sequencing analysis was performed at autopsy (n = 19) or postnatally (n = 1) on 20 fetuses. Of the 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, nine (47%) had positive genetic results, including one with a pathogenic copy number variant and eight with pathogenic/likely pathogenic variants. Non-sarcomere gene mutations accounted for the vast majority (n = 7). In contrast, sarcomere gene mutations occurred in only one case (TPM1), and no mutations were identified in the three most common sarcomere genes (MYH7, TTN, and MYBPC3) of pediatric and adult patients. Pathogenic/likely pathogenic variants were significantly more frequent in fetuses with congenital heart defects than those without congenital heart defects.Conclusions: Our data demonstrate that fetal NCCM is a unique entity. Compared with pediatric and adult NCCM, fetal NCCM is more prone to biventricle involvement, more likely to be complicated with congenital heart defects, and has a distinct genetic spectrum.

scholarly journals Screening of 22q11.2DS Using Multiplex Ligation-Dependent Probe Amplification as an Alternative Diagnostic Method

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Sathiya Maran ◽  
Siti Aisyah Faten ◽  
Swee-Hua Erin Lim ◽  
Kok-Song Lai ◽  
Wan Pauzi Wan Ibrahim ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Diagnostic Method ◽  
Heart Defects ◽  
22Q11.2 Deletion Syndrome ◽  
Confirmatory Test ◽  
Deletion Syndrome ◽  
Molecular Diagnostic ◽  
Nonallelic Homologous Recombination ◽  
Dependent Probe

Background. The 22q11.2 deletion syndrome (22q11.2DS) is the most common form of deletion disorder in humans. Low copy repeats flanking the 22q11.2 region confers a substrate for nonallelic homologous recombination (NAHR) events leading to rearrangements which have been reported to be associated with highly variable and expansive phenotypes. The 22q11.2DS is reported as the most common genetic cause of congenital heart defects (CHDs). Methods. A total of 42 patients with congenital heart defects, as confirmed by echocardiography, were recruited. Genetic molecular analysis using a fluorescence in situ hybridization (FISH) technique was conducted as part of routine 22q11.2DS screening, followed by multiplex ligation-dependent probe amplification (MLPA), which serves as a confirmatory test. Results. Two of the 42 CHD cases (4.76%) indicated the presence of 22q11.2DS, and interestingly, both cases have conotruncal heart defects. In terms of concordance of techniques used, MLPA is superior since it can detect deletions within the 22q11.2 locus and outside of the typically deleted region (TDR) as well as duplications. Conclusion. The incidence of 22q11.2DS among patients with CHD in the east coast of Malaysia is 0.047. MLPA is a scalable and affordable alternative molecular diagnostic method in the screening of 22q11.2DS and can be routinely applied for the diagnosis of deletion syndromes.

scholarly journals The study of copy number variations in the regions of PRKAB2 and PPM1K among congenital heart defects patients

2019 ◽  
Vol 65 (6) ◽  
pp. 786-790
Author(s):  
Han-Quan Dong ◽  
Yue-Xin Du
Keyword(s):  
Ventricular Septal Defect ◽  
Tetralogy Of Fallot ◽  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Septal Defect ◽  
Heart Defects ◽  
Copy Number Variations ◽  
Chinese Han ◽  
Han Population

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.

scholarly journals Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

2016 ◽  
Vol 135 (3) ◽  
pp. 273-285 ◽  
Author(s):  
Elisabeth E. Mlynarski ◽  
◽  
Michael Xie ◽  
Deanne Taylor ◽  
Molly B. Sheridan ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Copy Number Variants ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion

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

2016 ◽  
Vol 36 (2) ◽  
pp. 177-185 ◽  
Author(s):  
Fenna A. R. Jansen ◽  
Mariette J. V. Hoffer ◽  
Christine L. van Velzen ◽  
Stephani Klingeman Plati ◽  
Marry E. B. Rijlaarsdam ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Chromosomal Abnormalities ◽  
Heart Defects ◽  
Copy Number Variations

scholarly journals Systemic Screening for 22q11.2 Copy Number Variations in Hungarian Pediatric and Adult Patients With Congenital Heart Diseases Identified Rare Pathogenic Patterns in the Region

2021 ◽  
Vol 12 ◽  
Author(s):  
Gloria Kafui Esi Zodanu ◽  
Mónika Oszlánczi ◽  
Kálmán Havasi ◽  
Anita Kalapos ◽  
Gergely Rácz ◽  
...  
Keyword(s):  
Genetic Screening ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Heart Defects ◽  
Screening Method ◽  
Copy Number Variations ◽  
Deletion Syndrome ◽  
Chromosomal Microarray Analysis ◽  
Pathogenic Cnvs

Congenital heart defects (CHD) are the most common developmental abnormalities, affecting approximately 0.9% of livebirths. Genetic factors, including copy number variations (CNVs), play an important role in their development. The most common CNVs are found on chromosome 22q11.2. The genomic instability of this region, caused by the eight low copy repeats (LCR A-H), may result in several recurrent and/or rare microdeletions and duplications, including the most common, ∼3 Mb large LCR A-D deletion (classical 22q.11.2 deletion syndrome). We aimed to screen 22q11.2 CNVs in a large Hungarian pediatric and adult CHD cohort, regardless of the type of their CHDs. All the enrolled participants were cardiologically diagnosed with non-syndromic CHDs. A combination of multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray analysis and droplet digital PCR methods were used to comprehensively assess the detected 22q11.2 CNVs in 212 CHD-patients. Additionally, capillary sequencing was performed to detect variants in the TBX1 gene, a cardinal gene located in 22q11.2. Pathogenic CNVs were detected in 5.2% (11/212), VUS in 0.9% and benign CNVs in 1.8% of the overall CHD cohort. In patients with tetralogy of Fallot the rate of pathogenic CNVs was 17% (5/30). Fifty-four percent of all CNVs were typical proximal deletions (LCR A-D). However, nested (LCR A-B) and central deletions (LCR C-D), proximal (LCR A-D) and distal duplications (LCR D-E, LCR D-H, LCR E-H, LCR F-H) and rare combinations of deletions and duplications were also identified. Segregation analysis detected familial occurrence in 18% (2/11) of the pathogenic variants. Based on in-depth clinical information, a detailed phenotype–genotype comparison was performed. No pathogenic variant was identified in the TBX1 gene. Our findings confirmed the previously described large phenotypic diversity in the 22q11.2 CNVs. MLPA proved to be a highly efficient genetic screening method for our CHD-cohort. Our results highlight the necessity for large-scale genetic screening of CHD-patients and the importance of early genetic diagnosis in their clinical management.

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