Body Region Dysmorphology Is Predictive of Genetic Diagnoses in Infants With Congenital Heart Disease

Genetic causes of congenital heart disease (CHD) are often underrecognized, though precision phenotyping may improve screening for genetic disorders. We demonstrate how body region dysmorphology predicts genetic diagnoses associated with CHD.

We used a test-negative case-control study of CHD infants undergoing standardized genetics evaluations. We investigated correlations between body region dysmorphology (BRD) and CHD classes and developed novel models for predicting genetic diagnoses, including cytogenetic/monogenic disorders identified by genetic testing.

In 243/1008 patients with genetic diagnoses (24.1%), we found novel correlations between BRDs and CHD classes. Periorbital, maxilla/midface, ear, and mandible BRDs correlated with conotruncal CHD with genetic diagnoses (25.5%); left ventricular outflow tract CHD presented with few BRDs despite genetic diagnoses identified (18.5%). Septal and right ventricular outflow tract CHD had a wider spectrum of BRDs. Multivariable modeling identified multiple BRDs predicting genetic diagnoses, including of the face (OR = 2.57), forehead (OR = 2.55), neck (OR = 2.24), periorbital (OR = 1.57), and hands/feet (OR = 1.90) regions, after adjusting for extracardiac anomalies (OR = 3.65), CHD class (p = 0.02), and male sex (OR = 0.69). The BRD model had acceptable utility assessed by decision curve analysis. Face/forehead/neck BRDs predicted cytogenetic and monogenic diagnoses (ORs ranging 2.2-2.5), though BRDs of hands/feet associated with cytogenetic disorders (OR = 2.22). Males were less likely to have cytogenetic diagnoses compared to females (OR = 0.59), suggesting potential sex-specific differences.

This is a novel investigation of body region dysmorphology patterns predictive of genetic diagnoses in CHD patients. Precision phenotyping can be an important part of care and allow clinicians to risk-stratify young CHD patients suspected of having genetic disorders.