scholarly journals Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009679
Author(s):  
Enrique Audain ◽  
Anna Wilsdon ◽  
Jeroen Breckpot ◽  
Jose MG Izarzugaza ◽  
Tomas W. Fitzgerald ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
De Novo ◽  
Integrative Analysis ◽  
Disease Genes ◽  
Rare Cnvs ◽  
Genomic Deletions ◽  
Genomic Variants ◽  
New Associations

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

scholarly journals Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

2020 ◽  
Author(s):  
E Audain ◽  
A Wilsdon ◽  
J Breckpot ◽  
JMG Izarzugaza ◽  
TW Fitzgerald ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
De Novo ◽  
Notch Signaling Pathway ◽  
Integrative Analysis ◽  
Disease Genes ◽  
Genomic Deletions ◽  
Genomic Variants ◽  
New Associations

AbstractCongenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

scholarly journals Correction: Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009809
Author(s):  
Enrique Audain ◽  
Anna Wilsdon ◽  
Jeroen Breckpot ◽  
Jose M. G. Izarzugaza ◽  
Tomas W. Fitzgerald ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Integrative Analysis ◽  
Genomic Variants ◽  
New Associations

scholarly journals High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jun-yi Zhu ◽  
Yulong Fu ◽  
Margaret Nettleton ◽  
Adam Richman ◽  
Zhe Han
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Throughput ◽  
Congenital Heart ◽  
De Novo ◽  
Disease Risk ◽  
In Vivo Model ◽  
Disease Genes ◽  
Specific Patient

Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. We describe the first high throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors.

scholarly journals Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ekanem N. Ekure ◽  
Adebowale Adeyemo ◽  
Hanhan Liu ◽  
Ogochukwu Sokunbi ◽  
Nnenna Kalu ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Exome Sequencing ◽  
Congenital Heart ◽  
De Novo ◽  
Sub Saharan Africa ◽  
Disease Genes ◽  
Loss Of Function ◽  
Unique Identifier ◽  
Sub Saharan

Background: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease. Methods: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference–based gene silencing system. Results: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (s het ). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD ( UBB, EIF4G3, SREBF1 , and METTL23 ). Conclusions: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01952171.

scholarly journals Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

2021 ◽  
Author(s):  
Barbara Gonzalez-Teran ◽  
Maureen Pittman ◽  
Franco Felix ◽  
Desmond Richmond-Buccola ◽  
Reuben Thomas ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Large Scale ◽  
De Novo ◽  
Affinity Purification ◽  
Missense Variant ◽  
Disease Genes ◽  
Cardiac Progenitors ◽  
Affinity Purification Mass Spectrometry

SUMMARYCongenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.

scholarly journals De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
W. Scott Watkins ◽  
E. Javier Hernandez ◽  
Sergiusz Wesolowski ◽  
Brent W. Bisgrove ◽  
Ryan T. Sunderland ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Genetic Architecture ◽  
Congenital Heart ◽  
De Novo ◽  
Disease Genes ◽  
Compound Heterozygous ◽  
Modifying Genes ◽  
Whole Exome ◽  
Background Mutation Rate

Abstract The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD.

scholarly journals Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Begona Sanchez-Lechuga ◽  
Muhammad Saqlain ◽  
Nicholas Ng ◽  
Kevin Colclough ◽  
Conor Woods ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Case Report ◽  
Congenital Heart ◽  
De Novo ◽  
Adult Onset ◽  
Onset Diabetes ◽  
Adult Onset Diabetes ◽  
Pancreatic Agenesis

scholarly journals Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoxian Deng ◽  
Shanshan Li ◽  
Qiu Qiu ◽  
Bowen Jin ◽  
Menghuan Yan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Congenital Heart ◽  
Pediatric Patients ◽  
De Novo ◽  
Wide Spectrum ◽  
Heart Defects ◽  
Pulmonary Arterial

Abstract Background Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. Case presentation The patient was a 8-month-old female with repeated episodes of pneumonia. Physical examination revealed cleft lip, cleft palate and developmental retardation. Imaging examination showed a small atrial septal defect (ASD), central pulmonary artery enlargement, left upper lobe of lung atelectasis, and pulmonary infiltration. Genetic test showed she carried a de novo pathogenic variant of FLNA gene (c.5417-1G > A, p.-). Oral medications didn’t slow the progression of PAH in the patient, and she died two years later. Conclusions FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other comorbidities in pediatric patients. We highly recommend genetic testing for pediatric patients when suspected with PAH. Given the high mortality in this group, lung transplantation may offer a better outcome.

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