LBX2 – Atrial Septal Defect, Ostium Secundum Type

This summary describes the association between LBX2 (HGNC:15525) and ostium secundum atrial septal defect (MONDO_0020434) based on evidence from case reports, multi-patient studies, and functional assessments. In a Chinese family, whole exome sequencing of three affected members (PMID:29669692) revealed a rare missense mutation in LBX2 that segregated with the disease. Additionally, screening in 300 unrelated patients identified two further sporadic cases carrying LBX2 variants (PMID:29669692).

Genetic evidence is bolstered by the identification of the variant c.415A>G (p.Lys139Glu) in the mutation list. This variant was found in the family and reproduced in sporadic cases, indicating a recurrent association between LBX2 defects and atrial septal defect. The robust familial segregation, with at least two additional affected relatives showing the variant (PMID:29669692), supports a strong genetic component.

Functional studies further reinforce the association. LBX2 knockout zebrafish models exhibited an expanded atrium and ventricle along with abnormally organized cardiac myocytes. Such phenotypic alterations in cardiac development, as well as delayed migration of neural crest cells in the embryo, were observed and align with the clinical manifestations of ASD (PMID:29669692). The experimental data strongly support a pathogenic mechanism whereby LBX2 deficiency disrupts normal cardiac septation.

The overall ClinGen gene-disease association is classified as Strong because multiple lines of evidence—including genetic segregation in a familial context (3 probands) and corroborative functional assays—converge to confirm LBX2’s role in atrial septal defect. Though additional studies in other phenotypes (e.g., abdominal aortic aneurysm, gastric cancer) have described LBX2 functions, these do not conflict with its causal role in ASD.

Integrating the genetic and experimental findings, the data indicate that LBX2 mutations, particularly the c.415A>G (p.Lys139Glu) variant, precipitate disruptions in cardiac septation through impaired cardiac neural crest cell migration. This integrated evidence supports the diagnostic inclusion of LBX2 in genetic testing panels for atrial septal defect, especially the ostium secundum type.

Key take‑home sentence: LBX2 is a clinically relevant gene for atrial septal defect (ostium secundum type), with strong genetic and supportive functional evidence, meriting its use in diagnostic decision‑making and targeted therapeutic development.

References

• International journal of cardiology • 2018 • Identification of LBX2 as a novel causal gene of atrial septal defect PMID:29669692
• Biomedicine & pharmacotherapy • 2020 • LncRNA LBX2-AS1 facilitates abdominal aortic aneurysm through miR-4685-5p/LBX2 feedback loop PMID:32559617
• Gastric cancer • 2020 • LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop contributes to the proliferation of gastric cancer PMID:31673844

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