Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.
Jorge L GranadilloWendy K ChungLeah HechtNicole Corsten-JanssenDaniel WegnerSebastiaan W A Nij BijvankTomi L TolerDaniel E Pineda-AlvarezGanka DouglasJoshua J MurphyJoshua ShimonyMarwan S ShinawiPublished in: Human mutation (2018)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- late onset
- weight gain
- copy number
- congenital heart disease
- signaling pathway
- case report
- coronary artery
- body mass index
- ejection fraction
- end stage renal disease
- early onset
- mental health
- newly diagnosed
- heart failure
- birth weight
- immune response
- aortic valve
- pulmonary artery
- dna methylation
- left ventricular
- pi k akt
- patient reported outcomes
- big data
- cell proliferation
- pulmonary arterial hypertension
- genome wide
- patient reported
- growth hormone