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

Kai Luo, Chenqing Zheng, Rong Luo, Xin Cao, Huajun Sun, Huihui Ma, Jichang Huang, Xu Yang, Xiushan Wu, Xiaoping Li
2022 unpublished
BackgroundFamilial 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.MethodsWhole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We
more » ... en 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.ResultsWe 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. Conclusionswe present the first finding of an autosomal recessive BICD2 variant that is associated with familial DCM, providing further insight into the molecular pathological mechanism of DCM.
doi:10.21203/ fatcat:6qxq2gy73nfwhanyvdywzg7ceu