Abstract 20150: Whole Exome Sequencing, Genomic Triangulation, and Systems Biology Converge to Identify TAB2 as a Novel Susceptibility Gene for Polyvalvular Syndrome
Introduction: The genetic basis for polyvalvular syndrome remains elusive. A male child was born with polyvalvular syndrome, aortic root dilatation, and an ASD, VSD, and PDA that were surgically closed. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, Noonan syndrome (NS) or Williams syndrome (WS) spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available NS and WS genetic tests were negative.
Methods: Whole exome sequencing (WES) of the patient and both parents was performed. Considering the negative family history, a sporadic de novo mechanism was hypothesized and absence in the parental genomes was required for consideration as a putative pathogenic mutation. An additional requirement was absence in over 7595 publically available exomes from the 1000 Genomes project (1kG, N=1092) and the NHLBI Exome Sequencing project (ESP, N=6503).
Results: A sporadic de novo mutation, annotated as c. 1491 T>A, in TAB2, resulting in a nonsense mutation, p. Y497X, in the TAB2-encoded TAK1 binding protein 2 was identified as the most likely disease-susceptibility gene. This nonsense mutation was absent in the public exomes, including 4679 Caucasian exomes. Further, no TAB2 early terminating mutations were identified in the public exomes. This nonsense mutation results in a premature truncation of this 693-amino acid containing protein, eliminating the terminal 197 amino acids and truncating the C-terminal binding motif responsible for critical interactions with TRAF6 and TAK1. Previously, two missense mutations, P208S and Q230K, have been reported in one patient with subaortic stenosis and a second patient with bicuspid aortic valve and aortic dilation, respectively.
Conclusions: The combination of whole exome sequencing, genomic triangulation, and systems biology have uncovered perturbations in TAK1 signaling as a novel pathogenic substrate for polyvalvular syndrome. The TAB2-associated phenotypic spectrum may depend on the severity of the signaling insult. The spectrum and prevalence of TAB2 mutations among unrelated patients with polyvalvular syndrome remains to be determined.
Author Disclosures: J.A. Smestad: None. J.D. Kapplinger: None. D.J. Tester: Other; Modest; Transgenomic. B.A. Crabb: None. N.J. Mendelsohn: Research Grant; Significant; Sanofi-Genzyme, BioMarin, Shire. Honoraria; Significant; BioMarin. Consultant/Advisory Board; Significant; Shire. M.J. Ackerman: Consultant/Advisory Board; Modest; Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical. Other; Significant; Transgenomic.
- © 2014 by American Heart Association, Inc.