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JCDD, Vol. 10, Pages 455: TGFBR1 Variants Can Associate with Non-Syndromic Congenital Heart Disease without Aortopathy
Journal of Cardiovascular Development and Disease doi: 10.3390/jcdd10110455
Authors: Manal Alaamery Nour Albesher Fahad Alhabshan Phil Barnett Mohamed Salim Kabbani Farah Chaikhouni Aho Ilgun Olaf R. F. Mook Hessa Alsaif Vincent M. Christoffels Peter van Tintelen Arthur A. M. Wilde Arjan C. Houweling Salam Massadeh Alex V. Postma
Background: Congenital heart diseases (CHD) are the most common congenital malformations in newborns and remain the leading cause of mortality among infants under one year old. Molecular diagnosis is crucial to evaluate the recurrence risk and to address future prenatal diagnosis. Here, we describe two families with various forms of inherited non-syndromic CHD and the genetic work-up and resultant findings. Methods: Next-generation sequencing (NGS) was employed in both families to uncover the genetic cause. In addition, we performed functional analysis to investigate the consequences of the identified variants in vitro. Results: NGS identified possible causative variants in both families in the protein kinase domain of the TGFBR1 gene. These variants occurred on the same amino acid, but resulted in differently substituted amino acids (p.R398C/p.R398H). Both variants co-segregate with the disease, are extremely rare or unique, and occur in an evolutionary highly conserved domain of the protein. Furthermore, both variants demonstrated a significantly altered TGFBR1-smad signaling activity. Clinical investigation revealed that none of the carriers had (signs of) aortopathy. Conclusion: In conclusion, we describe two families, with various forms of inherited non-syndromic CHD without aortopathies, associated with unique/rare variants in TGFBR1 that display altered TGF-beta signaling. These findings highlight involvement of TGFBR1 in CHD, and warrant consideration of potential causative TGFBR1 variants also in CHD patients without aortopathies.
