Congenital heart defects (CHDs) are the most common congenital anomalies, with identifiable genetic etiologies in approximately 5–30% of affected infants, depending on the clinical presentation and comorbidities. This study included 216 children with CHD, predominantly syndromic, to explore the role of genetic variants in their morphological phenotypes. Chromosomal microarray (CMA) and whole-exome sequencing (WES) were performed, revealing clinically significant copy number variations (csCNVs) in 27.3% of patients, with the most common deletions at 22q11.21 (11.9%) and 7q11.23 (8.5%). WES was conducted in 28.0% of cases, achieving a detection rate of 29.5%, primarily identifying variants related to Noonan syndrome. Genetic diagnoses were confirmed in 33.3% of patients, with clinically significant CNVs and SNV/INDELs found exclusively in those with syndromic CHD, leading to a 36.5% diagnosis rate in those patients. The identified variants most frequently affected genes encoding transcription factors (40.4%), followed by genes involved in the RAS signaling pathway and structural proteins (17.0%), and chromatin remodeling proteins (12.8%).

Congenital heart defects (CHDs) are the most common congenital anomalies, with identifiable genetic etiologies in approximately 5–30% of affected infants, depending on the clinical presentation and comorbidities. This study included 216 children with CHD, predominantly syndromic, to explore the role of genetic variants in their morphological phenotypes. Chromosomal microarray (CMA) and whole-exome sequencing (WES) were performed, revealing clinically significant copy number variations (csCNVs) in 59 (27.3%) patients. The most frequent were 22q11.21 (8/59; 13.6%) and 7q11.23 (5/59; 8.5%) deletions. WES was conducted in 28.0% of cases, achieving a detection rate of 29.5%, primarily identifying variants related to Noonan syndrome. Genetic diagnoses were confirmed in 33.3% of patients, with clinically significant CNVs and SNV/INDELs found exclusively in those with syndromic CHD, leading to a 36.5% diagnosis rate in those patients. The identified variants most frequently affected genes encoding transcription factors (40.4%), followed by genes involved in the RAS signaling pathway and structural proteins (17.0%), and chromatin remodeling proteins (12.8%).