A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family

Abstract

Background: TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Case presentation: Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as "pathogenic" according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conclusion: We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.

Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

“…This approach yielded 252 proteins in total, which comprised several of the previously reported GATA4 and TBX5 interactors as well as novel interactors (Enane et al, 2017;Padmanabhan et al, 2020;Waldron et al, 2016). Mutations in several of these interactors have been already associated to human or mouse cardiac malformations, highlighting the potential of our approach for disease-gene discovery (Jin et al, 2017;Bouman et al, 2017;Castillo-Robles et al, 2018;Chen et al, 2020;Diets et al, 2019;Dsouza et al, 2019;Ferrante et al, 2006;Gordillo et al, 1993;Hinton et al, 2014;Homsy et al, 2015;Ji et al, 2020;Jones et al, 2012;Lebrun et al, 2018;Lei et al, 2012;Lepore et al, 2006;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Takeuchi et al, 2011;Thienpont et al, 2010;Van Dijck et al, 2019;Wilczewski et al, 2018) (Figure 1B and1C, Figure S2A and S2B…”

“…Since several of the GT-interactors with CHD-associated DNVs have previously been implicated in human cardiac malformations ( Figure S3A) (Bouman et al, 2017;Chen et al, 2020;Ji et al, 2020;Jin et al, 2017;Jones et al, 2012;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Thienpont et al, 2010), we sought to determine whether the enrichment was predominately driven by genes previously known to be involved in cardiac development or CHD by removing them from the dataset and repeating the permutation-based analysis (Table S5). We still found a significant enrichment in proteins harboring protein-altering DNVs from CHD probands in both GATA4 and TBX5 interactomes (adjusted OR G-PPI: 5.17; T-PPI: 3.38) ( Figure 2B and Table S4).…”

“…We thank Francoise Chanut for manuscript editorial support and Ana Catarina Silva (triangle), GATA4 (circle) or GATA4&TBX5 (square) networks. Red highlights proteins encoded by genes involved in human CHD (Bouman et al, 2017;Chen et al, 2020;Ji et al, 2020;Jin et al, 2017;Jones et al, 2012;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Thienpont et al, 2010). Edges represent protein-protein interactions from iRefIndex database (Razick et al, 2008).…”

“…The copyright holder for this preprint this version posted January 5, 2021. (A) GT-interactors with CHD-associated DNVs previously implicated in human cardiac malformations (Bouman et al, 2017;Chen et al, 2020;Jin et al, 2017;Jones et al, 2012;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Thienpont et al, 2010).…”

“…(D) Immunoprecipitation of GATA4 from enriched nuclear lysates of WT or GATA4-KO hiPSCderived cardiac progenitors (CPs; differentiation day 6), followed by immunoblotting with anti- (Bouman et al, 2017;Chen et al, 2020;Jin et al, 2017;Jones et al, 2012;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Thienpont et al, 2010).…”