LBX2 and Atrial Septal Defect

In a recent study investigating the genetic basis of atrial septal defect (ASD), LBX2 has emerged as a novel candidate gene. The study identified a heterozygous missense variant in LBX2 in a Chinese family with ASD, where three affected family members were evaluated (PMID:29669692). Subsequent screening of 300 unrelated patients with ASD revealed two additional missense variants in three cases, further supporting the role of LBX2 in this condition. This clustering of variants in affected individuals provides compelling clinical evidence for the gene–disease relationship.

Detailed genetic analysis pinpointed a specific coding change, reported as c.415A>G (p.Lys139Glu), after removal of extraneous transcript information. This variant was assessed in the context of other LBX2 missense mutations, and the segregation among affected relatives (with two additional affected individuals beyond the proband) reinforces autosomal dominant inheritance. The genetic evidence is supported by robust case–control screening, where the mutation was absent in 400 normal controls, underscoring its pathogenic significance (PMID:29669692).

The mode of inheritance for LBX2-related atrial septal defect appears to be autosomal dominant, as demonstrated by familial segregation in the index family. The observed co-segregation of the variant with the disorder in multiple family members provides critical support for its clinical relevance. With two additional affected relatives showing the mutation beyond the proband, the genetic architecture aligns with dominant transmission, a pattern common in congenital cardiac malformations.

Complementary functional studies using LBX2 knockout zebrafish further substantiate the gene’s role in cardiac development. In these models, lbx2 deficiency resulted in an expanded atrium and ventricle, as well as disorganized myocardial architecture observed via histological examination. These phenotypic alterations mimic key aspects of human atrial septal defect, indicating that LBX2 is essential for proper cardiac septation (PMID:29669692).

Additional experimental evidence from in situ hybridization assays revealed that LBX2 deficiency leads to delayed migration of cardiac neural crest cells during embryogenesis. Such delay compromises the timely septation of the heart, thereby providing a plausible mechanistic link between the identified genetic variation and the observed congenital malformation. Overall, the functional insights add an important layer of biological plausibility to the gene–disease association.

In conclusion, the integration of genetic and functional data establishes a strong association between LBX2 (HGNC:15525) and atrial septal defect (MONDO_0006664). The discovery of the c.415A>G (p.Lys139Glu) variant with familial segregation, combined with zebrafish knockout data that recapitulate the human phenotype, underscores the clinical utility of incorporating LBX2 into diagnostic panels. Key take‑home sentence: LBX2 is a clinically actionable gene for atrial septal defect, with robust evidence supporting its pathogenic role in cardiac development.

References

• International journal of cardiology • 2018 • Identification of LBX2 as a novel causal gene of atrial septal defect PMID:29669692

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