Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Cardiovascular Biology

Background:

• SMAD2 is a key mediator of the transforming growth factor-beta (TGF-β) signaling pathway, crucial for embryonic development, tissue differentiation, and pattern formation.
• Previous studies have associated pathogenic variants in SMAD2 with arterial aneurysms, dissections, and complex congenital heart disease (CHD).

Observation:

• Whole exome sequencing (WES) was employed to identify the genetic basis of congenital anomalies in four patients.
• Three patients presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain, or fetal complex CHD with heterotaxy.
• The fourth patient, an adult female, exhibited an aortic root aneurysm and features indicative of a connective tissue disorder.

Findings:

• WES identified pathogenic variants in SMAD2, including truncating, splice, and predicted deleterious missense variants, in all four patients.
• The study identified two distinct phenotypes associated with pathogenic SMAD2 variants: complex CHD (with or without laterality defects and other congenital anomalies) and a late-onset vascular phenotype (arterial aneurysms with connective tissue abnormalities).

Implications:

• These findings expand the understanding of the genotype-phenotype spectrum for SMAD2-related disorders.
• Identifying pathogenic SMAD2 variants aids in diagnosing complex CHD and connective tissue disorders, potentially guiding clinical management and genetic counseling.
• Further research into SMAD2 function may reveal therapeutic targets for these conditions.