Functional analysis of novel genetic variants of <i><scp>NKX2</scp>‐5</i> associated with nonsyndromic congenital heart disease

Dixit, Ritu B.; Narasimhan, Chitra; Balekundri, Vijayalakshmi I; Agrawal, D. P.; Kumar, Ashok; Mohapatra, Bhagyalaxmi

doi:10.1002/ajmg.a.62413

Cited by 12 publications

(7 citation statements)

References 85 publications

(143 reference statements)

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“…NKX2-5 is a transcription factor previously demonstrated to have highly specific expression in heart tissue, which is in congruence with the fact that this gene belongs to the top quantile (40) within both our specificity quantile and mean expression quantile metrics. This gene was in fact the first known genetic risk factor for congenital heart disease, and its expression is necessary not only for the development of cardiomyocytes but also the continued functioning of heart cells into adulthood 32,33 .…”

Section: Exemplar Results Identify Known Associations While Revealing...mentioning

confidence: 99%

Identification of cell type-specific gene targets underlying thousands of rare diseases and subtraits

Murphy

Gordon-Smith

Chapman

et al. 2023

Preprint

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Rare diseases (RDs) are uncommon as individual diagnoses, but as a group contribute to an enormous disease burden globally. However, partly due the low prevalence and high diversity of individual RDs, this category of diseases is understudied and under-resourced. The advent of large, standardised genetics databases has enabled high-throughput, comprehensive approaches that uncover new insights into the multi-scale aetiology of thousands of diseases. Here, using the Human Phenotype Ontology (9,677 annotated phenotypes) and multiple single-cell transcriptomic atlases (77 human cell types and 38 mouse cell types), we conducted >688,000 enrichment tests (x100,000 bootstrap iterations each) to identify >13,888 genetically supported cell type-phenotype associations. Our results recapitulate well-known cell type-phenotype relationships, and extend our understanding of these diseases by pinpointing the genes linking phenotypes to specific cell (sub)types. We also reveal novel cell type-phenotype relationships across disparate branches of clinical disease (e.g. the nervous, cardiovascular, and immune systems). Next, we introduce a computational pipeline to prioritise gene targets with high cell type-specificity to minimise off-target effects and maximise therapeutic potential. To broaden the impact of our study, we have released two R packages to fully replicate our analyses, as well as a series of interactive web apps so that stakeholders from a variety of backgrounds may further explore and utilise our findings. Together, we present a promising avenue for systematically and robustly uncovering the multi-scale aetiology of RDs at scale.

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Section: Exemplar Results Identify Known Associations While Revealing...mentioning

confidence: 99%

Identification of cell type-specific gene targets underlying thousands of rare diseases and subtraits

Murphy

Gordon-Smith

Chapman

et al. 2023

Preprint

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“…Studies have shown a specific involvement in the development of the outflow tract and the right ventricle while also regulating the formation of the conduction system [52][53][54]. Approximately 2-4% of all CHDs can be associated with SNPs in the NKX2-5 gene [17], particularly linked with septal defects (ASDs and VSDs) or outflow tract defects (tetralogy of Fallot, double-outlet right ventricle, and transposition of the great arteries) [55,56]. CNVs involving this gene were also reported; one patient carrying a triplication of the 5q35.3 region, including the NKX2-5 gene, was found through MLPA screening of a CHD multicentric cohort.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects

Bolunduț,

Nazarie,

Lazea

et al. 2024

Genes

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Congenital heart defects (CHDs) have had an increasing prevalence over the last decades, being one of the most common congenital defects. Their etiopathogenesis is multifactorial in origin. About 10–15% of all CHD can be attributed to copy number variations (CNVs), a type of submicroscopic structural genetic alterations. The aim of this study was to evaluate the involvement of CNVs in the development of congenital heart defects. We performed a cohort study investigating the presence of CNVs in the 22q11.2 region and GATA4, TBX5, NKX2-5, BMP4, and CRELD1 genes in patients with syndromic and isolated CHDs. A total of 56 patients were included in the study, half of them (28 subjects) being classified as syndromic. The most common heart defect in our study population was ventricular septal defect (VSD) at 39.28%. There were no statistically significant differences between the two groups in terms of CHD-type distribution, demographical, and clinical features, with the exceptions of birth length, weight, and length at the time of blood sampling, that were significantly lower in the syndromic group. Through multiplex ligation-dependent probe amplification (MLPA) analysis, we found two heterozygous deletions in the 22q11.2 region, both in patients from the syndromic group. No CNVs involving GATA4, NKX2-5, TBX5, BMP4, and CRELD1 genes were identified in our study. We conclude that the MLPA assay may be used as a first genetic test in patients with syndromic CHD and that the 22q11.2 region may be included in the panels used for screening these patients.

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“…The nkx2.5 and sox9b genes play important regulatory roles in the differentiation of cardiac precursor cells, the circularization of the heart, the formation of the atrioventricular septum, and the maintenance of mature cardiac function [ 44 , 45 ]. We examined the mRNA levels of these genes and found that melatonin blunted the arsenite-induced low expression.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis

et al. 2022

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Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10−9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.

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Functional analysis of novel genetic variants of NKX2‐5 associated with nonsyndromic congenital heart disease

Cited by 12 publications

References 85 publications

Identification of cell type-specific gene targets underlying thousands of rare diseases and subtraits

Identification of cell type-specific gene targets underlying thousands of rare diseases and subtraits

A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects

Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis

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