TY - JOUR
T1 - TGFBR1 Variants Can Associate with Non-Syndromic Congenital Heart Disease without Aortopathy
AU - Alaamery, Manal
AU - Albesher, Nour
AU - Alhabshan, Fahad
AU - Barnett, Phil
AU - Salim Kabbani, Mohamed
AU - Chaikhouni, Farah
AU - Ilgun, Aho
AU - Mook, Olaf R F
AU - Alsaif, Hessa
AU - Christoffels, Vincent M
AU - van Tintelen, Peter
AU - Wilde, Arthur A M
AU - Houweling, Arjan C
AU - Massadeh, Salam
AU - Postma, Alex V
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/11/9
Y1 - 2023/11/9
N2 - 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.
AB - 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.
KW - TGFBR1
KW - TGFbeta-smad signaling
KW - congenital heart defect
KW - gain of function
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85178147040&partnerID=8YFLogxK
U2 - 10.3390/jcdd10110455
DO - 10.3390/jcdd10110455
M3 - Article
C2 - 37998513
SN - 2308-3425
VL - 10
JO - Journal of Cardiovascular Development and Disease
JF - Journal of Cardiovascular Development and Disease
IS - 11
M1 - 455
ER -