Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation

Vad, Oliver Bundgaard; Yan, Yannan; Denti, Federico; Ahlberg, Gustav; Refsgaard, Lena; Bomholtz, Sofia Hammami; Santos, Joana Larupa; Rasmussen, Simon; Haunsø, Stig; Svendsen, Jesper Hastrup; Christophersen, Ingrid E; Schmitt, Nicole; Olesen, Morten S.; Bentzen, Bo Hjorth

doi:10.3389/fgene.2022.806429

Cited by 2 publications

(1 citation statement)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, aggregating investigations have convincingly substantiated that genetic determinants exert critical roles in the initiation and perpetuation of AF, especially for idiopathic/familial AF, and, to date, a great number of rare AF-causing variations in >60 genes have been causally related to AF, amidst which the overwhelming majority encode ion channel subunits, myocardial structural proteins, signaling molecules, cardiac transcription factors, and connexins [ 52 , 53 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. In addition, pan-genomic association research has revealed that common variants at ~140 genetic loci are implicated with enhanced vulnerability to AF, though merely a small fraction of these recognized variants have been experimentally validated to be pathogenic for AF thus far [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Li,

Guo

et al. 2023

Biology

View full text Add to dashboard Cite

Atrial fibrillation (AF), the most prevalent type of sustained cardiac dysrhythmia globally, confers strikingly enhanced risks for cognitive dysfunction, stroke, chronic cardiac failure, and sudden cardiovascular demise. Aggregating studies underscore the crucial roles of inherited determinants in the occurrence and perpetuation of AF. However, due to conspicuous genetic heterogeneity, the inherited defects accounting for AF remain largely indefinite. Here, via whole-genome genotyping with genetic markers and a linkage assay in a family suffering from AF, a new AF-causative locus was located at human chromosome 7p14.2-p14.3, a ~4.89 cM (~4.43-Mb) interval between the markers D7S526 and D7S2250. An exome-wide sequencing assay unveiled that, at the defined locus, the mutation in the TBX20 gene, NM_001077653.2: c.695A>G; p.(His232Arg), was solely co-segregated with AF in the family. Additionally, a Sanger sequencing assay of TBX20 in another family suffering from AF uncovered a novel mutation, NM_001077653.2: c.862G>C; p.(Asp288His). Neither of the two mutations were observed in 600 unrelated control individuals. Functional investigations demonstrated that the two mutations both significantly reduced the transactivation of the target gene KCNH2 (a well-established AF-causing gene) and the ability to bind the promoter of KCNH2, while they had no effect on the nuclear distribution of TBX20. Conclusively, these findings reveal a new AF-causative locus at human chromosome 7p14.2-p14.3 and strongly indicate TBX20 as a novel AF-predisposing gene, shedding light on the mechanism underlying AF and suggesting clinical significance for the allele-specific treatment of AF patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Li,

Guo

et al. 2023

Biology

View full text Add to dashboard Cite

show abstract

Identification and Functional Investigation of SOX4 as a Novel Gene Underpinning Familial Atrial Fibrillation

Jiang,

Sun,

Qiu

et al. 2024

Diagnostics

View full text Add to dashboard Cite

Background: Atrial fibrillation (AF) signifies the most prevalent supraventricular arrhythmia in humans and may lead to cerebral stroke, cardiac failure, and even premature demise. Aggregating strong evidence points to genetic components as a cornerstone in the etiopathogenesis of familial AF. However, the genetic determinants for AF in most patients remain elusive. Methods: A 4-generation pedigree with idiopathic AF and another cohort of 196 unrelated patients with idiopathic AF as well as 278 unrelated healthy volunteers were recruited from the Chinese population of Han ethnicity. A family-based whole-exome sequencing examination followed by a Sanger sequencing assay in all research subjects was implemented. The functional impacts of the identified SOX4 mutations were explored via a dual-reporter assay. Results: Two new heterozygous SOX4 mutations, NM_003107.3: c.211C>T; p.(Gln71*) and NM_003107.3: c.290G>A; p.(Trp97*), were observed in the family and 1 of 196 patients with idiopathic AF, respectively. The two mutations were absent in the 278 control individuals. The biochemical measurements revealed that both Gln71*- and Trp97*-mutant SOX4 failed to transactivate GJA1 (Cx43). Moreover, the two mutations nullified the synergistic activation of SCN5A by SOX4 and TBX5. Conclusions: The findings first indicate SOX4 as a gene predisposing to AF, providing a novel target for antenatal genetic screening, individualized prophylaxis, and precision treatment of AF.

show abstract

Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation

Cited by 2 publications

References 33 publications

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation

Identification and Functional Investigation of SOX4 as a Novel Gene Underpinning Familial Atrial Fibrillation

Contact Info

Product

Resources

About