Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS

Zhao, Yingjie; Wang, Yujue; Shi, Lijie; McDonald‐McGinn, Donna M.; Crowley, T. Blaine; McGinn, Daniel; Tran, Oanh; Miller, Daniella; Lin, Jhih-Rong; Zackai, Elaine H.; Johnston, H. Richard; Chow, Eva W.C.; Vorstman, Jacob; Vingerhoets, Claudia; Amelsvoort, Thérèse van; Gothelf, Doron; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris Robert; Eliez, Stéphan; Schneider, Maude; Bree, Marianne Bernadette van den; Kates, Wendy R.; Repetto, Gabriela M.; Shashi, Vandana; Schoch, Kelly; Bearden, Carrie E.; Digilio, María Cristina; Unolt, Marta; Putotto, Carolina; Marino, Bruno; Pontillo, Maria; Armando, Marco; Vicari, Stefano; Angkustsiri, Kathleen; Campbell, Linda E.; Busa, Tiffany; Heine-Suñer, Damián; Murphy, Kieran C.; Murphy, Declan; García‐Miñaúr, Sixto; Fernández, Luís; Zhang, Zhengdong D.; Goldmuntz, Elizabeth; Gur, Raquel E.; Emanuel, Beverly S.; Zheng, Deyou; Marshall, Christian R.; Bassett, Anne S.; Wang, Tao; Morrow, Bernice E.

doi:10.1038/s41525-023-00363-y

Cited by 3 publications

(5 citation statements)

References 67 publications

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“…Conotruncal defects are caused by the underdevelopment or misalignment of the ventricular septum, outflow tract, and/or great arteries, such as tetralogy of Fallot, patent truncus arteriosus, and transposition of the great arteries (see Figure 13). Autosomal dominant 22q11.2 deletion syndrome often leads to conotruncal defects, which are commonly associated with the deletion of the CHD-associated gene TBX1 [131][132][133][134]. Similarly, CHARGE syndrome, which is often caused by deletions or variants in the CHD-associated gene CHD7 [135][136][137][138], can also result in conotruncal defects.…”

Section: Conotruncal Defectsmentioning

confidence: 99%

“…The congenital heart defects mentioned display variable penetrance and expressivity [138][139][140], indicating that additional factors influence the clinical phenotype. A genetic modifier that influences conotruncal defects in 22q11.2 deletion syndrome has been reported, although these additional factors are largely unknown [131,141]. Repetitive duplications and deletions at 1q21.1, which involve the CHD candidate genes GJA5 (encoding connexin 40) and CHD1L (linked to the CHD7 gene), are frequently associated Autosomal dominant 22q11.2 deletion syndrome often leads to conotruncal defects, which are commonly associated with the deletion of the CHD-associated gene TBX1 [131][132][133][134].…”

Section: Conotruncal Defectsmentioning

confidence: 99%

“…A genetic modifier that influences conotruncal defects in 22q11.2 deletion syndrome has been reported, although these additional factors are largely unknown [131,141]. Repetitive duplications and deletions at 1q21.1, which involve the CHD candidate genes GJA5 (encoding connexin 40) and CHD1L (linked to the CHD7 gene), are frequently associated Autosomal dominant 22q11.2 deletion syndrome often leads to conotruncal defects, which are commonly associated with the deletion of the CHD-associated gene TBX1 [131][132][133][134]. Similarly, CHARGE syndrome, which is often caused by deletions or variants in the CHDassociated gene CHD7 [135][136][137][138], can also result in conotruncal defects.…”

Section: Conotruncal Defectsmentioning

confidence: 99%

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In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

Nappi

2024

IJMS

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The use of next-generation sequencing has provided new insights into the causes and mechanisms of congenital heart disease (CHD). Examinations of the whole exome sequence have detected detrimental gene variations modifying single or contiguous nucleotides, which are characterised as pathogenic based on statistical assessments of families and correlations with congenital heart disease, elevated expression during heart development, and reductions in harmful protein-coding mutations in the general population. Patients with CHD and extracardiac abnormalities are enriched for gene classes meeting these criteria, supporting a common set of pathways in the organogenesis of CHDs. Single-cell transcriptomics data have revealed the expression of genes associated with CHD in specific cell types, and emerging evidence suggests that genetic mutations disrupt multicellular genes essential for cardiogenesis. Metrics and units are being tracked in whole-genome sequencing studies.

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Section: Conotruncal Defectsmentioning

confidence: 99%

Section: Conotruncal Defectsmentioning

confidence: 99%

Section: Conotruncal Defectsmentioning

confidence: 99%

See 1 more Smart Citation

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

Nappi

2024

IJMS

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“…Autosomal dominant 22q11.2 deletion syndrome often leads to conotruncal defects, which are commonly associated with the deletion of the CHD-associated gene TBX1. [131][132][133][134] Similarly, CHARGE syndrome, which is often caused by deletions or variants in the CHD-associated gene CHD7, [135][136][137][138] can also result in conotruncal defects. These disorders are associated with cardiac, facial and head malformations, which originate in neural crest cells, and reveal effects of harmful gene variants on cell lineages involved in extra-cardiac malformations.…”

Section: Conotruncal Defectsmentioning

confidence: 99%

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

Nappi

2024

Preprint

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New insights into the causes and mechanisms of congenital heart disease (CHD) have been gained through the use of next-generation sequencing. Examination of the whole exome sequence detects detrimental gene variations modifying single or contiguous nucleotides, that are characterised as pathogenicity based on statistical assessments of families. and correlates with congenital heart disease, elevated expression during heart development, and reduction of harmful protein-coding mutations in the general population. Patients with CHD and extracardiac abnormalities enriched for gene classes meeting these criteria. CHDs and extracardiac defects, supporting a common set of pathways in the organogenesis of CHDs. Single-cell transcriptomics data reveal the expression of genes associated with CHD in specific cell lineages, and emerging evidence suggests that genetic variants disrupt multicellular genes essential for cardiogenesis. Metrics and units are being tracked in whole genome sequence studies.

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“…Smyk et al (2023) [14] reported that 6.3% of individuals with 22q11.2DS had additional CNVs likely contributing to the clinical presentation. Zhao et al (2023) [15] demonstrated that disruptions in chromatin regulatory genes affect the TBX1 gene network, suggesting shared mechanisms between the TBX1 gene network and the etiology of congenital heart diseases (CDH). Additionally, some studies have provided compelling evidence indicating that microRNA dysregulation is implicated in the development of schizophrenia in 22q11.2DS patients [16,17].…”

Section: Introductionmentioning

confidence: 99%

22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity

de Wallau,

Xavier,

Moreno

et al. 2024

Genes

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22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

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Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS

Cited by 3 publications

References 67 publications

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity

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