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Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia

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Abstract

Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype. Results showed that a novel heterozygous single-nucleotide duplication (c.128dup) and a novel heterozygous missense (c.3328A > G) variant in ABCA5 gene were identified in the proband. The single-nucleotide duplication (c.128dupT), inherited from his father and patrilineal grandfather, leads to a frameshift which results into the formation of a truncated ABCA5 protein of 50 (p.Leu43Phefs*8) amino acids. Hence, it is a loss-of-function mutation. The missense (c.3328A > G) variant, inherited from his mother, leads to the replacement of isoleucine by valine at the position of 1110 (p.Ile1110Val) of the ABCA5 protein. Multiple sequence alignment showed that p.Ile1110 is evolutionarily conserved among several species indicating both the structural and functional significance of the p.Ile1110 residue in the wild-type ABCA5 protein. Quantitative RT-PCR showed that the ABCA5 mRNA expression levels were decreased in the proband. These two novel variants of ABCA5 gene were co-segregated well among all the members of this family. Our present study also strongly supports the importance of using family-based whole genome sequencing for identifying novel candidate genes associated with IVT.

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Abbreviations

IVT:

Idiopathic ventricular tachycardia

WGS:

Whole genome sequencing

WES:

Whole exome sequencing

SNV:

Single-nucleotide variant

INDEL:

Insertion/deletion

CHD:

Congenital heart disease

SCD:

Sudden cardiac death

VF:

Ventricular fibrillation

ECG:

Electrocardiographic

ACMG:

American college of medical genetics and genomics

VUS:

Variant of uncertain significance

DCM:

Dilated cardiomyopathy

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Acknowledgements

We are thankful to the proband and all the family members for participating in our study. We are thankful to the China National GeneBank and Shenzhen Peacock Plan (No. KQTD20150330171505310).

Funding

The National Natural Science Foundation, China (81570287, 81770315, 81770316) and Taishan Scholarship, Shandong, China (Silin Pan).

Author information

Author notes

  1. Zhanhui Du, Shan Kuang and Yong Li contributed equally for this work.

Authors and Affiliations

  1. Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, 266034, China

    Zhanhui Du & Silin Pan

  2. BGI-Qingdao, BGI-Shenzhen, 2877 Tuanjie Road, Sino-German Ecopark, Qingdao, 266555, China

    Shan Kuang, Yong Li, Peng Han, Junnian Liu, Zhiwei Wang, Yingping Huang, Yuanning Guan, Xun Xu, Xin Liu & Santasree Banerjee

  3. China National Gene Bank, BGI-Shenzhen, Shenzhen, 518120, China

    Shan Kuang, Yong Li, Peng Han, Junnian Liu, Zhiwei Wang, Yingping Huang, Yuanning Guan, Xun Xu, Xin Liu & Santasree Banerjee

  4. BGI-Shenzhen, Shenzhen, 518083, China

    Junnian Liu, Xun Xu, Xin Liu & Santasree Banerjee

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  1. Zhanhui Du
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  2. Shan Kuang
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  3. Yong Li
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  9. Xun Xu
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  10. Xin Liu
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  11. Santasree Banerjee
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  12. Silin Pan
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Contributions

SB and SP designed the study. Z conducted acquisition and analysis of all the clinical data. YH, PH, and YG made WES pipeline. SB, SK, YL, JL, and ZW analyzed the data. SB, SK, and YL wrote the manuscript. XL and XX supervised manuscript preparation and edited the manuscript.

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Correspondence to Santasree Banerjee or Silin Pan.

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Du, Z., Kuang, S., Li, Y. et al. Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia. Pediatr Cardiol 41, 1783–1794 (2020). https://doi.org/10.1007/s00246-020-02446-4

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