Identification and functional characterization of BICD2 as a candidate disease gene in an consanguineous family with dilated cardiomyopathy

Background Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed. Methods Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq. Results We identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism. Conclusions Our study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.

Automated summary

In this study, the researchers identified BICD2 as a novel candidate gene associated with familial dilated cardiomyopathy (DCM). Through whole-exome sequencing and zebrafish models, they discovered an autosomal recessive missense variant in the BICD2 gene that correlated with the disease phenotype of DCM. Further investigation using the zebrafish models revealed that bicd2 knockout resulted in heart dilation and decreased cardiac function, resembling the phenotype of human DCM. Gene expression analysis also showed significant alterations in cardiac pathways and mitochondrial energy metabolism in bicd2-deficient fish.