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Published on: March 10, 2020
Functional analysis of HECA variants identified in congenital heart disease in the Chinese population
Ting Li1,2, Yao Wu1, Wei-Cheng Chen1,2
1Children's Hospital of Fudan University, Shanghai, China.
Insights
This study identifies mutations in the HECA gene associated with congenital heart disease (CHD). HECA gene variants impact cardiomyocyte function and cell cycle progression, expanding the genetic landscape of CHD.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Congenital heart disease (CHD) encompasses various cardiovascular defects.
- The role of the HECA gene, a novel cell cycle regulator, in CHD remains unexplored.
Purpose of the Study:
- To investigate the frequency of HECA gene mutations in patients with CHD.
- To determine the association between HECA variants and the risk of developing CHD.
- To elucidate the functional impact of HECA gene abnormalities on cardiomyocyte behavior.
Main Methods:
- Whole-exome sequencing identified HECA as a candidate gene in an atrial septal defect family.
- Targeted exon sequencing analyzed 689 individuals with sporadic CHD for HECA variants.
- Functional analyses included Western blotting, RT-qPCR, and scratch assays to assess HECA's effect on cardiomyocyte phenotype and signaling pathways.
Main Results:
- A novel de novo HECA mutation (c.409_410insA, p.W137fs) and five rare deleterious variants were identified in individuals with sporadic CHD.
- HECA variations showed a significant association with CHD compared to the East Asian population in gnomADv2 (p=0.0027).
- HECA deficiency disrupted cardiomyocyte cell cycle progression, enhanced proliferation and migration, and activated the PDGF-BB/PDGFRB/AKT pathway.
Conclusions:
- The study identified HECA and six rare variants, broadening the genetic basis of CHD pathogenesis.
- These findings highlight HECA as a potential contributor to CHD in the Chinese population.
Background:
Congenital heart disease (CHD) is a class of cardiovascular defects that includes septal defects, outflow tract abnormalities, and valve defects. Human homolog of Drosophila headcase (HECA) is a novel cell cycle regulator whose role in CHD has not been elucidated. This is the first study to determine the frequency of HECA mutations in patients with CHD and the association between HECA variants and CHD.
Methods:
In this study, we identified a candidate gene, HECA, by whole-exome sequencing of an atrial septal defect family. To investigate the association between HECA variants and CHD risk, targeted exon sequencing was conducted in 689 individuals with sporadic CHD. We further analyzed the effect of HECA gene abnormalities on cardiomyocyte phenotype behavior and related signaling pathways by Western blotting, reverse transcription-quantitative polymerase chain reaction, and scratch assay.
Results:
We found a novel de novo mutation, c.409_410insA (p. W137fs), in the HECA gene and identified five rare deleterious variants that met the filtering criteria in 689 individuals with sporadic CHD. Fisher's exact test revealed a significant association between HECA variations and CHD compared with those in gnomADv2-East Asians(p = 0.0027). Further functional analysis suggested that the variant p. W137fs resulted in a deficiency of the normal HECA protein, and HECA deficiency altered AC16 cell cycle progression, increased cell proliferation, and migration, and promoted the activation of the PDGF-BB/PDGFRB/AKT pathway.
Conclusions:
Our study identified HECA and its six rare variants, expanding the spectrum of genes associated with CHD pathogenesis in the Chinese population.
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