Key result
LAMA3 nonsense variants link to familial Ebstein's anomaly and cause Ebstein's malformation in mice.
Why the study?
The genetic basis of Ebstein’s anomaly has yet to be fully elucidated despite known contributions from several genes.
Identifies a novel gene-disease association between LAMA3 variants and Ebstein's anomaly, highlighting the role of the extracellular matrix in its etiology.
LAMA3 variants may underlie Ebstein's anomaly; hypothesis-generating and requires human validation before any clinical use.
Ebstein’s anomaly is a rare congenital heart disease characterized by tricuspid valve downwards displacement and was 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 3α (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.
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Zhou et al. (2023) studied Ebstein's anomaly. Heterozygous nonsense variants in laminin subunit 3α (LAMA3) was evaluated on Ebstein's anomaly phenotypes. Heterozygous nonsense variants in laminin subunit 3α (LAMA3) were identified in two families with Ebstein's anomaly, and Lama3 haploinsufficiency in mice led to Ebstein's malformation.
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