Frontiers in genetics · 2025
Optical genome mapping uncovers clinically relevant structural variants in congenital heart disease with heterotaxy.
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Min Shaojie, Sun Jingwei, Chen Weicheng, Feng Zhiyu, Zhuang Quannan, Gao Yuan, Lin Siyi, Sun Siyu, Lu Yuquan, Li Shuolin, Tian Xueying, Huang Guoying, Sheng Wei, Huang Xianghui
Аннотация
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 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 microarray analysis (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.
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 microarray analysis (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.