Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

Turki, Saeed Al; Manickaraj, Ashok Kumar; Mercer, Catherine; Gerety, Sebastian S.; Hitz, Marc-Phillip; Lindsay, Sarah; D’Alessandro, Lisa C.A.; Swaminathan, Ganesh; Bentham, Jamie; Arndt, Anne-Karin; Louw, Jacoba; Breckpot, Jeroen; Gewillig, Marc; Thienpont, Bernard; Abdul‐Khaliq, Hashim; Harnack, Christine; Hoff, Kirstin; Kramer, Hans‐Heiner; Schubert, Stephan; Siebert, Reiner; Toka, Okan; Cosgrove, Catherine; Watkins, Hugh; Lucassen, Anneke; O’Kelly, Ita; Salmon, Anthony P.; Bu’Lock, Frances; Granados-Riverón, Javier T.; Setchfield, Kerry; Thornborough, Chris; Brook, J. David; Mulder, Barbara J.M.; Klaassen, S.; Bhattacharya, Shoumo; Devriendt, Koen; FitzPatrick, David R.; Wilson, D.I.; Mital, Seema; Hurles, Matthew E.

doi:10.1016/j.ajhg.2016.02.016

Cited by 8 publications

(7 citation statements)

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“…BMP7 codes a ligand of growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis, and skeletal morphogenesis [28]. Diseases associated with BMP7 include multiple types of congenital heart defects [29]. FMN2 encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity.…”

Section: Ingenuity Pathway Analysismentioning

confidence: 99%

DNA Methylation Patterns in Umbilical Cord Blood from Infants of Methadone Maintained Opioid Dependent Mothers

Adegboyega,

Betal,

Urday

et al. 2024

Preprint

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Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference > + 2, < -2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.

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Section: Ingenuity Pathway Analysismentioning

confidence: 99%

DNA Methylation Patterns in Umbilical Cord Blood from Infants of Methadone Maintained Opioid Dependent Mothers

Adegboyega,

Betal,

Urday

et al. 2024

Preprint

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“…Furthermore, many of the patient's phenotypes could be explained by dysregulation of genes in potentially affected TADs. The MCTP2 gene (orange gene on left side) is associated with several of the patient's phenotypes including “abnormal aortic arch morphology” (HP:0012303), “coarctation of aorta” (HP:0001680), “patent ductus arteriosus” (HP:0001643), and “bicuspid aortic valve” (HP:0001647), and the NR2F2 gene (orange gene on right side) is associated with “coarctation of aorta.” Prior studies suggest that heterozygous mutations in MCTP2 and NR2F2 can lead to cardiac abnormalities (Al Turki et al., 2014; Lalani et al., 2013). Finally, the statistics function showed that the weighted HPO score for this variant is higher at its actual location than at 497 out of 500 random locations.…”

Section: Commentarymentioning

confidence: 99%

A Guide to Using ClinTAD for Interpretation of DNA Copy Number Variants in the Context of Topologically Associated Domains

Spector

Wiita

2020

CP Human Genetics

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DNA copy number variants (CNVs) are routinely evaluated as part of clinical diagnosis in both the prenatal and postnatal genetic settings. Current guidelines for interpreting the potential clinical significance of these CNVs, typically identified by chromosomal microarray, focus entirely on genes localized within the CNV region. However, recent work has suggested that some CNVs can actually produce clinical impacts by influencing transcription of genes outside the CNV region. These alterations of transcription appear to occur by disrupting the composition of DNA topologically associated domains (TADs), which strongly influence contacts between gene promoters and their associated enhancers. Here we present a set of detailed protocols for the use of the free software tool ClinTAD (https:// www.clintad.com). This decision-support software allows for prediction as to whether a given CNV may potentially disrupt a TAD boundary, and offers phenotype matching to genes near, but not within the CNV region, whose expression could be influenced by altered TAD architecture and that have phenotypic impacts related to that reported in a given patient. Our protocols here provide specific examples of how to implement these tools. In addition, the software has the capability to impact genomic research by evaluating multiple cases in parallel. We propose that this decision-support tool can benefit and improve genetic diagnosis.

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“…COUP-TFII (encoded by NR2F2) plays a role in angiogenesis, vascular remodeling, and heart development as well as in more widespread regulation of cell fate during embryonic development. Recently, heterozygous variants in NR2F2 have been reported in patients with a range of congenital cardiac disease phenotypes (68). In one family, a 3-bp duplication in NR2F2 segregated with multiple cardiac defects (i.e., atrioventricular septal defect [AVSD], aortic stenosis/VSD, and tetralogy of Fallot), whereas other heterozygous missense mutations or deletions of NR2F2 have been associated with AVSD, hypoplastic left heart syndrome, or aortic coarctation (68).…”

Section: Coup-tfiimentioning

confidence: 99%

“…Recently, heterozygous variants in NR2F2 have been reported in patients with a range of congenital cardiac disease phenotypes (68). In one family, a 3-bp duplication in NR2F2 segregated with multiple cardiac defects (i.e., atrioventricular septal defect [AVSD], aortic stenosis/VSD, and tetralogy of Fallot), whereas other heterozygous missense mutations or deletions of NR2F2 have been associated with AVSD, hypoplastic left heart syndrome, or aortic coarctation (68). Congenital diaphragmatic hernia may be an association in mice and humans (69).…”

Section: Coup-tfiimentioning

confidence: 99%

Genetic disorders of nuclear receptors

Achermann¹,

Schwabe²,

Fairall³

et al. 2017

Journal of Clinical Investigation

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Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.

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Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

Cited by 8 publications

References 0 publications

DNA Methylation Patterns in Umbilical Cord Blood from Infants of Methadone Maintained Opioid Dependent Mothers

DNA Methylation Patterns in Umbilical Cord Blood from Infants of Methadone Maintained Opioid Dependent Mothers

A Guide to Using ClinTAD for Interpretation of DNA Copy Number Variants in the Context of Topologically Associated Domains

Genetic disorders of nuclear receptors

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