Comprehensive analysis of copy number variations in congenital heart defects Tunisian patients: chromosomal...

Congenital heart defects represent a major global health burden, affecting nearly one million newborns annually. Identifying the underlying genetic causes is essential for improved diagnosis, patient management, and genetic counseling.

We conducted a cytogenetic study integrating conventional karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA 44 K) in 20 Tunisian patients presenting syndromic CHDs and referred to our Genetics Department.

CMA identified pathogenic copy number variations in four patients. These included an inherited 11 Mb deletion at 9p24.2 together with a 10 Mb duplication of 20pter; a de novo 1.2 Mb deletion at 15q26.2 with an 11 Mb duplication at 2q36.3; a de novo 113 kb deletion at 17q21.32; and a de novo 48 Mb duplication at 8q22. Several CNVs overlapped known deletion/duplication syndromes, some with previously infrequent cardiac involvement. Genotype-phenotype correlations enabled prioritization of CHD relevant genes including DOCK8, HTR2B, KANSL1, ZFPM2, and TRPS1, whose dosage sensitivity and interactions with cardiac developmental pathways may contribute to the observed phenotypes.

This study reinforces the clinical utility of CMA in detecting cryptic chromosomal abnormalities in syndromic CHD. The identified CNVs and gene candidates offer new insights into CHD genetic architecture and support CMA as a first-tier diagnostic tool. These findings highlight the contribution of rare, pathogenic CNVs in syndromic cases and suggest their integration into refined diagnostic and counseling strategies. Further functional studies are necessary to elucidate the roles of these candidates in cardiogenesis.