Severe coarctation of the aorta, developmental delay, and multiple dysmorphic features in a child with SMAD6 and...

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Cardiology

Background:

• Pathogenic variants in SMARCA4 are associated with Coffin-Siris syndrome (CSS).
• Variants in SMAD6 are linked to aortic valve disease and dysmorphic features.
• Combined genetic variants can lead to complex and overlapping phenotypes.

Purpose of the Study:

• To report a novel case of a child with combined features of CSS and severe coarctation of the aorta (CoA).
• To investigate the genetic basis of unusual manifestations including bilateral radioulnar synostoses and severe CoA.
• To explore the potential synergistic effects of de novo variants in SMARCA4 and SMAD6.

Main Methods:

• Trio exome sequencing was performed to identify causative genetic variants.
• Clinical features were meticulously documented and correlated with identified genetic variants.
• Phenotypic analysis was conducted to compare with known features of SMARCA4 and SMAD6 variants.

Main Results:

• A 6-year-old Thai boy presented with CSS features, severe CoA requiring neonatal coarctectomy, and bilateral radioulnar synostoses.
• Trio exome sequencing identified two novel de novo variants: SMARCA4 p.(Trp825Cys) and SMAD6 p.(Gln218Ter).
• The SMARCA4 variant correlated with CSS features and Dandy-Walker malformation; the SMAD6 variant explained radioulnar synostosis. The severe CoA was potentially due to synergistic effects.

Conclusions:

• This case illustrates a unique presentation resulting from combined de novo variants in SMARCA4 and SMAD6.
• The severe coarctation of the aorta may arise from the additive or synergistic impact of both genetic variants.
• This finding expands the known phenotypic spectrum associated with SMARCA4 and SMAD6 variants and highlights the complexity of genetic interactions in developmental disorders.