Heterozygous nonsense variants in laminin subunit 3α resulting in Ebstein's anomaly.

Zhou Zhou, Xumei Huang, Xia Tang, Wen Chen, Qianlong Chen, Chaohui Zhang, Yuxin Li, Dachun Zhao, Zhe Zheng, Shengshou Hu, Jikui Wang, Iftikhar J Kullo, Keyue Ding

HGG advances 2023 Oct 12

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Ebstein's anomaly is a rare congenital heart disease characterized by tricuspid valve downward displacement and is associated with additional cardiac phenotypes such as left ventricle non-compaction. The genetic basis of Ebstein's anomaly has yet to be fully elucidated, although several genes (e.g., NKX2-5, MYH7, TPM1, and FLNA) may contribute to Ebstein's anomaly. Here, in two Ebstein's anomaly families (a three-generation family and a trio), we identified independent heterozygous nonsense variants in laminin subunit 3 α (LAMA3), cosegregated with phenotypes in families with reduced penetrance. Furthermore, knocking out Lama3 in mice revealed that haploinsufficiency of Lama3 led to Ebstein's malformation of the tricuspid valve and an abnormal basement membrane structure. In conclusion, we identified a novel gene-disease association of LAMA3 implicated in Ebstein's anomaly, and the findings extended our understanding of the role of the extracellular matrix in Ebstein's anomaly etiology. © 2023 The Author(s).

Citation

Zhou Zhou, Xumei Huang, Xia Tang, Wen Chen, Qianlong Chen, Chaohui Zhang, Yuxin Li, Dachun Zhao, Zhe Zheng, Shengshou Hu, Jikui Wang, Iftikhar J Kullo, Keyue Ding. Heterozygous nonsense variants in laminin subunit 3α resulting in Ebstein's anomaly. HGG advances. 2023 Oct 12;4(4):100227