Optical Genome Mapping Uncovers Clinically Relevant Structural Variants in Congenital Heart Disease with Heterotaxy

Shaojie Min¹Jingwei Sun²Weicheng Chen¹Zhiyu Feng¹Quannan Zhuang¹Yuan Gao¹Siyi Lin¹Siyu Sun¹Yuquan Lu¹Shuolin Li¹Xueying Tian³Guoying Huang^1,4,5Wei Sheng^1,4,5*Xianghui Huang^1,4*

• ¹Shanghai Key Laboratory of Birth Defects, Pediatric Heart Center, Children's Hospital of Fudan University, Shanghai, China
• ²Bengbu First People's Hospital, Bengbu, China
• ³Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
• ⁴Fujian Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University at Xiamen, Fujian, China
• ⁵Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, China

Introduction The genetic factors underlying congenital heart disease and heterotaxy (CHD/HTX) are complex, including copy number variants, loss-of-function mutations, and missense variants, many of which can be detected by the high throughput sequencing. The screening for chromosomal structural variations (SVs) is another important strategy to understand the genetic etiology of CHD/HTX. Methods We employed optical genome mapping (OGM), an innovative technique capable of capturing SVs often missed by traditional cytogenetic methods, to screen for SVs in 12 patients with complex CHD/HTX. Several patients had previously undergone chromosomal microarrays (CMA) or whole exome sequencing (WES), but their genetic diagnoses remained inconclusive. Results By integrating data from CMA or WES, we analyzed potentially pathogenic SVs in patients with CHD/HTX. In total, we identified 825 high-confidence SVs, including 609 SVs (73.7%) located in intergenic regions or containing introns, pseudogenes, or RNA genes, while 217 (26.3%) overlapped the coding regions of genes. Analyzed through AnnotSV, DECIPHER and OMIM databases, 7 SVs of interest were identified, including: one previously reported pathogenic SV, three SVs overlapping established CHD/HTX associated genes (NOTCH2, KDM6A and CBL), and three SVs located in SMARCA2 and CEP164, which are proposed as candidate susceptibility genes pending further validation. Conclusion Our findings highlight the utility of OGM in analyzing the genetic etiology of CHD/HTX and contribute to broadening of the complex genetic landscape underlying these diseases.