Introduction CNV is a vital pathogenic factor of congenital heart disease (CHD). However, few CNVs have been reported for total anomalous pulmonary venous connection (TAPVC), which is a rare form of CHD. Using case-control study, we identified 15q11.2 deletion associated with TAPVC. We then used a TAPVC trio as model to reveal possible molecular basis of 15q11.2 microdeletion.
Methods CNVplex and Chromosomal Microarray were used to identify and validate CNVs in samples from 231 TAPVC cases and 200 healthy controls from Shanghai Children’s Medical Center. In vitro cardiomyocyte differentiation of induced pluripotent stem cells from peripheral blood mononuclear cells for a TAPVC trio with paternal inherited 15q11.2 deletion was performed to characterise the effect of the deletion on cardiomyocyte differentiation and gene expression.
Results The 15q11.2 microdeletion was significantly enriched in patients with TAPVC compared with healthy control (13/231 in patients vs 0/200 in controls, p=5.872×10−2, Bonferroni adjusted) using Fisher’s exact test. Induced pluripotent stem cells from the proband could not differentiate into normal cardiomyocyte. Transcriptomic analysis identified a number of differentially expressed genes in the 15q11.2 deletion carriers of the family. TAPVC disease-causing genes such as PITX2, NKX2-5 and ANKRD1 showed significantly higher expression in the proband compared with her healthy mother. Knockdown of TUBGCP5 could lead to abnormal cardiomyocyte differentiation.
Conclusion We discovered that the 15q11.2 deletion is significantly associated with TAPVC. Gene expression profile that might arise from 15q11.2 deletion for a TAPVC family was characterised using cell experiments.
- congenital heart disease
- clinical genetics
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XL, GS and YL contributed equally.
Contributors Conceptualisation: BW, QF and HC. Formal analysis: BW and XL. Investigation: XL, GS, YL, XZ, YX, LY, TW and YX. Writing original draft preparation: XL. Writing review and editing: BW, QF, HZ, HC and YX.
Funding The work was supported by National Natural Science Foundation of China (81871717, 81672090).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Ethics Committee of the SCMC reviewed and approved this study (SCMCIRB-K2017009). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. Data are available on reasonable request. The high-throughput RNAseq data have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE136804. The Chromosomal Microarray CytoScan 750K data have been deposited in the ArrayExpress under accession code E-MTAB-8315. The whole exome sequencing raw data are available on reasonable request.