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.

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 Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Wang ◽  
Bin Zhang ◽  
Lingna Zhou ◽  
Qin Zhou ◽  
Yingping Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Screening ◽  
Comprehensive Evaluation ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Non Invasive ◽  
Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs > 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

scholarly journals A rare cardiac phenotype of dextrocardia observed in a fetus with 1p36 deletion syndrome and a balanced translocation: a prenatal case report

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Li Gao ◽  
Junyu Zhang ◽  
Xu Han ◽  
Wenjing Hu ◽  
Jinling Sun ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Deletion Syndrome ◽  
Chromosomal Microarray Analysis ◽  
Congenital Heart Diseases ◽  
Balanced Translocation ◽  
Cardiac Phenotype

Abstract Background Chromosome 1p36 deletion syndrome is a contiguous genetic disorder with multiple congenital anomalies and mental retardation. It has been emerging as one of the most common terminal deletion syndromes in humans with the rapid utility of microarray analysis. However, the prenatal findings of 1p36 deletion syndrome are still limited. We report a fetus with 1p36 deletion and cardiac phenotype of dextrocardia, combined with a balanced translocation between chromosome 5 and 6. The phenotype of dextrocardia is rarely reported in prenatal 1p36 deletion cases. Case presentation We present a prenatal 1p36 deletion case with congenital heart diseases and single umbilical artery. Fetal echocardiography showed dextrocardia, ventricular septal defect and pericardial effusion. Fetal karyotype revealed a de novo balanced translocation of 46,XY,t(5;6)(q11.2;q23.3). Chromosomal microarray analysis detected a pathogenic deletion in 1p36.21p36.12, with the size of 6.38 Mb. Further whole genome sequencing revealed that the balanced translocation disrupted the EYA4 and ITGA1 genes. Conclusions Although congenital heart diseases are very common clinical manifestations among patients with 1p36 deletion, dextrocardia is a quite rare cardiac phenotype. This is the second case with 1p36 deletion and dextrocardia, and the first prenatally diagnosed 1p36 deletion case with dextrocardia. Our case indicates that genes in 1p36 are associated with not only heart structural anomalies, but also cardiac laterality development. Our results also imply that the EYA4 gene disrupted by the balanced translocation might be related with the cardiac development.

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

scholarly journals Detection of Clinically Relevant Copy Number Variations and Genes in a Bangladeshi Cohort of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Hosneara Akter ◽  
Muhammad Mizanur Rahman ◽  
Shaoli Sarker ◽  
Mohammed Basiruzzaman ◽  
Mazharul Islam ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Critical Role ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Potential Candidate ◽  
Female Ratio ◽  
Pathogenic Cnvs

Abstract Background: Copy number variations (CNVs) play a critical role into the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple gene constraint metrics (i.e. “Critical-Exon Genes (CEGs)”) were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show severe social communication deficit (p=0.014) and overall ASD symptoms severity (p=0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs and identified PSMC3 gene as a potential candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis therapeutics and management of NDD patients.

scholarly journals Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

2016 ◽  
Vol 371 (1710) ◽  
pp. 20150406 ◽  
Author(s):  
Jason R. Cowan ◽  
Muhammad Tariq ◽  
Chad Shaw ◽  
Mitchell Rao ◽  
John W. Belmont ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Copy Number Variants ◽  
Loss Of Function ◽  
Pathogenic Cnvs ◽  
Number Variation ◽  
Left Right Asymmetry ◽  
Genomic Disorders

Genomic disorders and rare copy number abnormalities are identified in 15–25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left–right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 ( PFKP ) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

scholarly journals A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1048
Author(s):  
Ilse Meerschaut ◽  
Sarah Vergult ◽  
Annelies Dheedene ◽  
Björn Menten ◽  
Katya De Groote ◽  
...  
Keyword(s):  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Related Gene ◽  
Protein Coding ◽  
Gene Enhancer ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

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