<i>JAG1</i> Mutation in a patient with deletion 22q11.2 syndrome and tetralogy of Fallot

Digilio, María Cristina; Luca, Alessandro De; Lepri, Francesca; Guida, Valentina; Ferese, Rosangela; Dentici, Maria Lisa; Angioni, Adriano; Marino, Bruno; Dallapiccola, Bruno

doi:10.1002/ajmg.a.36148

Cited by 10 publications

(3 citation statements)

References 35 publications

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“…Point mutations of cardiac transcription factor genes, single nucleotide polymorphism (SNPs), aneuploidy, and chromosomal copy number variants (CNV) are directly associated with CHDs [41][42][43]. Similarly, mutations in genes encoding for receptors and ligands, which are responsible for cardiac morphogenesis signaling pathways such as Notch and Jagged respectively are implicated in the etiology of CHDs [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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Background: Congenital heart diseases (CHDs) are the most common congenital anomalies with an estimated prevalence of 8 in 1000 live births. CHDs occur as a result of abnormal embryogenesis of the heart. Congenital heart diseases are associated with significant mortality and morbidity. The damage of the heart is irreversible due to a lack of regeneration potential, and usually, the patients may require surgical intervention. Studying the developmental biology of the heart is essential not only in understanding the mechanisms and pathogenesis of congenital heart diseases but also in providing us with insight towards developing new preventive and treatment methods. Main body: The etiology of congenital heart diseases is still elusive. Both genetic and environmental factors have been implicated to play a role in the pathogenesis of the diseases. Recently, cardiac transcription factors, cardiacspecific genes, and signaling pathways, which are responsible for early cardiac morphogenesis have been extensively studied in both human and animal experiments but leave much to be desired. The discovery of novel genetic methods such as next generation sequencing and chromosomal microarrays have led to further study the genes, non-coding RNAs and subtle chromosomal changes, elucidating their implications to the etiology of congenital heart diseases. Studies have also implicated non-hereditary risk factors such as rubella infection, teratogens, maternal age, diabetes mellitus, and abnormal hemodynamics in causing CHDs. These etiological factors raise questions on multifactorial etiology of CHDs. It is therefore important to endeavor in research based on finding the causes of CHDs. Finding causative factors will enable us to plan intervention strategies and mitigate the consequences associated with CHDs. This review, therefore, puts forward the genetic and non-genetic causes of congenital heart diseases. Besides, it discusses crucial signaling pathways which are involved in early cardiac morphogenesis. Consequently, we aim to consolidate our knowledge on multifactorial causes of CHDs so as to pave a way for further research regarding CHDs. Conclusion: The multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and therefore plan intervention strategies. More well-designed studies and the use of novel genetic technologies could be the way through the discovery of etiological factors implicated in the pathogenesis of congenital heart diseases.

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Section: Introductionmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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“…Some genes are responsible for TOF, including mutations in NKX2.5,[15222627] GATA4 interacts physically with NKX2.5,[28] GATA6,[293031] JAG1,[11323334] JAG5,[35] TBX20,[36] BVES,[37] mitochondrial ATP8 gene,[38] epigenetic changes of some genes such as NKX2.5,[39] HAND1,[39] VANGL2,[40] and single nucleotide polymorphisms of some genes such as PTPN11[41] and MTHFR. [42] In addition, TOF has been observed to be concomitant with some syndromes and associations such as Down, Alagille, DiGeorge, and CHARGE syndromes, and VACTERL association.…”

Section: Discussionmentioning

confidence: 99%

Existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot

Kheirollahi

Khosravi

Ashouri³

et al. 2016

J Res Med Sci

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Background:Tetralogy of Fallot (TOF), the most common cyanotic heart defect and one of the most common congenital heart diseases, occurs mostly sporadically and nonsyndromically. The underlying molecular genetic mechanism is not known. Therefore, the existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot is evaluated.Materials and Methods:In the present study, we analyzed the peripheral blood samples of27 patients in order to find any mutation in the 180 bp homeodomain-encoding region of NKX2.5 gene, which is known to be involved in heart development and diseases. DNA was extracted and all the samples were amplified by polymerase chain reaction (PCR) and sequenced.Results:Twenty-seven patients were included in the study. Twenty-five of them were infants and children (6 days to 11 years of age), one was a teenager (14-years of age), and another was a 33-year-old man [mean ± standard deviation (SD): 5.80 ± 3.90 years]. Thirteen patents were males (mean ± SD: 6.587077 ± 5.02 years) and 14 were females (mean ± SD: 5.0726 ± 2.81 years). One synonymous variant, i.e., c.543G>A was identified in one patient.Conclusion:Mutations in the homeodomain-encoding region of NKX2.5 gene may not have an outstanding role in etiology of tetralogy of Fallot patients in Iran.

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“…epicardial and neural crest-derived signals (11). Mutations in notch signalling elements result in cHd in humans and mice, demonstrating its important role in normal cardiac development (12)(13)(14). noTcH4 serves as a membrane-bound receptor that regulates cell fate (15).…”

Section: Methylation Status Of Cpg Sites In the Notch4 Promoter Regiomentioning

confidence: 99%

Methylation status of CpG sites in the NOTCH4 promoter region regulates NOTCH4 expression in patients with tetralogy of Fallot

Zhu

et al. 2020

Mol Med Rep

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Tetralogy of Fallot (ToF) is the most common form of cyanotic congenital heart disease (cHd). although a lower methylation level of whole genome has been demonstrated in ToF patients, little is known regarding the dna methylation changes in specific gene and its associations with TOF development. noTcH4 is a mediator of the notch signalling pathway that plays an important role in normal cardiac development. However, the role of epigenetic regulation of the NOTCH4 gene in the pathogenesis of ToF remains unclear. considering the NOTCH4 low mutation frequency and reduced expression in the ToF patients, we hypothesized that abnormal dna methylation change of NOTCH4 gene may influence its expression and responsible for TOF development. in this study, we measured the promoter methylation status of NOTCH4 and was measured and its regulation mechanism was explored, which may be related to ToF disease. additionally, the promoter methylation statuses of NOTCH4 was measured in order to further understand epigenetic mechanisms that may serve a role in the development of ToF. immunohistochemical analysis was used to examine noTcH4 expression in right ventricular outflow tract myocardial tissues in patients with ToF. compared with healthy controls, patients with ToF displayed significantly reduced in noTcH4 expression (P=0.0055). Moreover, bisulphite sequencing suggested that the methylation levels of cpG site 2 in the NOTCH4 promoter was significantly higher in the patients than in the controls (P=0.0459). noTcH4 expression was negatively associated with cpG site 2 methylation levels (r=-0.51; P=0.01). eTS1 transcription factor can serve as transcriptional activators by binding to specific DNA sequences of target genes, such as DLL4 and NOTCH4, which serves an important role in normal heart development. dual-luciferase reporter and electrophoretic mobility shift assays indicated that the eTS1 transcription factor could bind to the NOTCH4 promoter region. However, binding of eTS1 to the NOTCH4 promoter was abrogated by methylation at the putative ETS1 binding sites. These findings suggested that decreased noTcH4 expression in patients with ToF may be associated with hypermethylation of cpG site 2 in the NOTCH4 promoter region, due to impaired binding of eTS1.

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JAG1 Mutation in a patient with deletion 22q11.2 syndrome and tetralogy of Fallot

Cited by 10 publications

References 35 publications

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Existence of mutations in the homeodomain-encoding region of NKX2.5 gene in Iranian patients with tetralogy of Fallot

Methylation status of CpG sites in the NOTCH4 promoter region regulates NOTCH4 expression in patients with tetralogy of Fallot

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