Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants

• Published in: Human mutation Vol. 39; no. 12; pp. 1875 - 1884
• Main Authors: Granadillo, Jorge L., Chung, Wendy K., Hecht, Leah, Corsten‐Janssen, Nicole, Wegner, Daniel, Nij Bijvank, Sebastiaan W.A., Toler, Tomi L., Pineda‐Alvarez, Daniel E., Douglas, Ganka, Murphy, Joshua J., Shimony, Joshua, Shinawi, Marwan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.12.2018
• Subjects: Adult; Alternative splicing; Aneurysm; Aneurysms; Aortic Aneurysm - genetics; arterial aneurysm; Body weight gain; Child; Child, Preschool; Congenital defects; congenital heart disease; Coronary artery disease; Exome; Exome Sequencing - methods; Female; Fetuses; Genetic Predisposition to Disease; Genotype; Genotypes; Heart Defects, Congenital - genetics; Heart diseases; heterotaxy; holoprosencephaly; Humans; Middle Aged; Mutation; Pattern formation; Phenotype; Phenotypes; Pregnancy; Seizures; Signal transduction; SMAD2; Smad2 protein; Smad2 Protein - genetics; SMAD2; congenital heart disease; mutation; holoprosencephaly; arterial aneurysm; heterotaxy
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.23627

SMAD2 is a downstream effector in the TGF‐β signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late‐onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities. The manuscript presents detailed clinical and molecular findings of four patients with novel SMAD2 predicted pathogenic variants detected through exome sequencing. The data show that pathogenic variants in SMAD2 are associated with two distinct phenotypes: complex congenital heart malformations with or without laterality defects and other congenital anomalies, and a late‐onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.