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

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

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.65.6.786 ◽

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.

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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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ENDOGENOUS RETROVIRUSES AS GENETIC MODULES THAT SHAPE THE GENOME REGULATORY NETWORKS DURING EVOLUTION

The Journal of V. N. Karazin Kharkiv National University, Series "Medicine" ◽

10.26565/2313-6693-2018-36-12 ◽

2018 ◽

Keyword(s):

Regulatory Networks ◽

Gene Activation ◽

Cell Types ◽

Regulatory Elements ◽

Endogenous Retroviruses ◽

Protein Coding ◽

Transcriptional Enhancers ◽

Wide Range ◽

Gene Regulatory Elements ◽

Gene Regulatory

Endogenous retroviruses (ERV) are the descendants of exogenous retroviruses that integrated into the germ cells genome, fixed and became inheritable. ERVs have evolved transcriptional enhancers and promoters that allow their replication in a wide range of tissue. Because ERVs comprise the regulatory elements it could be assume that ERVs capable to shape and reshape genomic regulatory networks by inserting their promoters and enhancers in new genomic loci upon retrotransposition. Thus retroransposition events can build new regulatory regions and lead to a new pattern of gene activation in the cell. In this review we summarize evidence which revealed that ERVs provide a plethora of novel gene regulatory elements, including tissue specific promoters and enhancers for protein-coding genes or long noncoding RNAs in a wide range of cell types. The accumulated findings support the hypothesis that the ERVs have rewired the gene regulatory networks and act as a major source of genomic regulatory innovation during evolution.

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

Prenatal Diagnosis ◽

10.1002/pd.4767 ◽

2016 ◽

Vol 36 (2) ◽

pp. 177-185 ◽

Cited By ~ 8

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

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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

Frontiers in Genetics ◽

10.3389/fgene.2021.635480 ◽

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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Development of Integrative Map of MicroRNA Gene Regulatory Elements

MicroRNA ◽

10.2174/2211536604666151002003003 ◽

2016 ◽

Vol 4 (3) ◽

pp. 205-208 ◽

Cited By ~ 4

Author(s):

Minja Zorc ◽

Tanja Kunej

Keyword(s):

Regulatory Elements ◽

Microrna Gene ◽

Gene Regulatory Elements ◽

Gene Regulatory

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Binding of an X-Specific Condensin Correlates with a Reduction in Active Histone Modifications at Gene Regulatory Elements

Genetics ◽

10.1534/genetics.119.302254 ◽

2019 ◽

Vol 212 (3) ◽

pp. 729-742 ◽

Cited By ~ 2

Author(s):

Lena Annika Street ◽

Ana Karina Morao ◽

Lara Heermans Winterkorn ◽

Chen-Yu Jiao ◽

Sarah Elizabeth Albritton ◽

...

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Chromatin Immunoprecipitation ◽

Protein Complexes ◽

Regulatory Elements ◽

Evolutionarily Conserved ◽

Chromatin Immunoprecipitation Sequencing ◽

Gene Regulatory Elements ◽

Gene Regulatory ◽

Regulatory Sites

Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In Caenorhabditis elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using chromatin immunoprecipitation sequencing and mRNA sequencing. Across the X, the DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. The DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.

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