Department of Cardiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, People's Republic of China.
Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, People's Republic of China.
BMC Med Genomics. 2022 Sep 6;15(1):189. doi: 10.1186/s12920-022-01349-y.
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.
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.
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.
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.
家族性扩张型心肌病（DCM）是一种遗传性心肌病，与左心室功能或收缩功能降低有关。已经报道了 51 个 DCM 致病基因，其中大多数以常染色体显性方式遗传。然而，很少观察到隐性 DCM 致病基因。
对一个 DCM 家系进行全外显子组测序（WES）以鉴定候选变异。通过 Sanger 测序验证该变异。然后我们在 210 例散发性 DCM 病例中检查了 DCM 候选基因。接下来，我们在胚胎和成年 bicd2 基因敲除斑马鱼模型中探索了 BICD2 的功能。通过超声心动图和 RNA-seq 检测 bicd2 基因敲除鱼的体内心脏功能。
我们在 BICD2 中发现了一个常染色体隐性和进化上保守的错义变异，NM_001003800.1:c.2429G>A，该变异在家系中与 DCM 表型共分离。此外，我们在 3 例散发性病例中证实了 BICD2 变异的存在。bicd2 基因敲除的纯合子在胚胎期部分致死，表明 bicd2 在胚胎发生中起着至关重要的作用。bicd2 基因敲除的斑马鱼出现心脏扩张和射血分数、心输出量和每搏输出量降低，提示类似于人类 DCM 的表型。此外，RNA-seq 证实 bicd2 纯合子的转录组变化大于杂合子。bicd2 缺陷鱼的基因集富集分析显示，心脏通路和线粒体能量代谢中基因表达的改变富集。
我们的研究首次表明 BICD2 是一个与家族性 DCM 相关的新候选基因，我们的发现将有助于进一步了解 DCM 的分子病理机制。
