Wenting Song1,2#, Shuang Zhou2#, Jieru Lu1,2, Yu Wang1,2, Qingjie Wang2, Jian Wang2, Zhuo Meng2, Jiayu Peng2, Yue Zhou2, Sun Chen2, Yurong Wu2* and Kun Sun1,2*
1Department of Pediatric Cardiology, Wenzhou Medical University, Second Affiliated Hospital, China
2Department of Pediatric Cardiovascular, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China
#These authors contributed equally to this work
Background: Conotruncal Defects (CTDs), caused by dysplasia of the Outflow Tract (OFT), are heterogeneous congenital heart malformations. Recent research has shown that Fibroblast Growth Factor 1 (FGFR1) is closely related to Endothelial-to-Mesenchymal Transition (EMT), which implies that dysfunctional FGFR1 can result in OFT malformation. Methods: FGFR1 variants were sequenced by targeted sequencing in a cohort of 604 CHD patients and population-matched healthy controls (n=300). To investigate the effect of mutations on the experience of the FGFR1 protein, as well as the influence of EMT related proteins in HUVECs. We also identified expression of FGFR1 in Carnegie stage 16 human embryos. Results: Three rare heterozygous non-synonymous variants were identified in six CTD patients: The variant NM_001174063: c.173G>A (p.R58Q), referred to as rs200116660; the variant NM_001174063: c.320C>T (p.S107L) referred to as rs140382957; and the variant NM_001174063: c1271 G>A (p.R333H), referred to as rs183376882. There was a difference in expression of the variants. The expression levels of EMT related genes in the variants were altered. And we found that FGFR1 was detected in the Outflow Tract (OFT) during human embryonic development. Conclusion: Our results demonstrate that the p.R58Q, p.S107L and p.R333H variants of FGFR1 contribute to CTD etiology by excessive suppression of EMT.
Song W, Zhou S, Lu J, Wang Y, Wang Q, Wang J, et al. Identification of FGFR1 Mutations in Patients with Sporadic Conotruncal Defect. Clin Surg. 2022; 7: 3415.