2015
DOI: 10.1007/s00439-015-1582-1
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Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome

Abstract: Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem c… Show more

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Cited by 73 publications
(87 citation statements)
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“…5c). A notable observation was the recovery of the Notch pathway, given previously reported findings of Notch1 variants in subjects with HLHS 10,11 , with 12 NOTCH-related mutations identified in 8 genes from 12 subjects (Supplementary Table 5). Also recovered were genes in the TGFβ pathway, with eight mutations in eight subjects (Supplementary Table 6).…”
mentioning
confidence: 81%
See 1 more Smart Citation
“…5c). A notable observation was the recovery of the Notch pathway, given previously reported findings of Notch1 variants in subjects with HLHS 10,11 , with 12 NOTCH-related mutations identified in 8 genes from 12 subjects (Supplementary Table 5). Also recovered were genes in the TGFβ pathway, with eight mutations in eight subjects (Supplementary Table 6).…”
mentioning
confidence: 81%
“…Mutations in five Notch-related genes ( Rbpj, Ep300, Nap1l1, Ncoa1 , and Tspan12 ), a pathway implicated in HLHS 10,11 , were identified. Network analysis 12 identified seven interconnected functional modules (0.64 modularity; 2.7 scaled modularity) significantly different from random networks (0.59 ± 0.019 modularity ( n = 1,000, mean ± s.d.…”
mentioning
confidence: 99%
“…tetralogy of Fallot)[13]. Additional reports support this finding that mutations in NOTCH1 cause malformations of the right and left sided cardiac outflow tract within families [11,14,15]. The other gene linked to BAV in humans is GATA5 , where rare sequence variants in GATA5 were identified in patients with BAV by multiple groups [16,17,18].…”
Section: Genetics Of Bicuspid Aortic Valvementioning
confidence: 96%
“…Among the different developmental signals (21)(22)(23), Wnt signaling pathways play prominent roles in cardiac precursor's commitment, cell proliferation, differentiation, and fate (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).Actions by the Wnt family molecules can be classified into the canonical Wnt/β-catenin-dependent pathway and the noncanonical pathway, which is generally β-catenin independent, and its function can be mediated by 2 distinct modules of the noncanonical signaling: (a) the planar cell polarity (PCP) pathway; and (b) the Wnt/ Ca 2+ pathway, which involves calmodulin-dependent kinase II (CamKII), protein kinase C (PKC), and calcineurin. These factors may coordinate important cellular signaling processes including regulating the expression of key cell cycle regulators.…”
Section: Introductionmentioning
confidence: 99%