PUBLICATION

Identification of novel candidate genes in heterotaxy syndrome patients with congenital heart diseases by whole exome sequencing

Authors
Liang, S., Shi, X., Yu, C., Shao, X., Zhou, H., Li, X., Chang, C., Lai, K.S., Ma, J., Zhang, R.
ID
ZDB-PUB-200802-10
Date
2020
Source
Biochimica et biophysica acta. Molecular basis of disease   1866(12): 165906 (Journal)
Registered Authors
Keywords
congenital heart disease, heterotaxy syndrome, rare variant, whole exome sequencing
MeSH Terms
  • Animals
  • Antigens/genetics
  • Cohort Studies
  • DNA-Binding Proteins/genetics*
  • Filamins/genetics*
  • Gene Editing
  • Heart Defects, Congenital/genetics*
  • Heterotaxy Syndrome/genetics*
  • Humans
  • Integrin alpha1/genetics
  • Kinesins/genetics*
  • Neoplasm Proteins/genetics*
  • Whole Exome Sequencing*
  • Zebrafish
  • Zinc Finger Protein GLI1/genetics*
PubMed
32738303 Full text @ BBA Molecular Basis of Disease
Abstract
Heterotaxy syndrome (HS) involves dysfunction of multiple systems resulting from abnormal left-right (LR) body patterning. Most HS patients present with complex congenital heart diseases (CHD), the disability and mortality of HS patients are extremely high. HS has great heterogeneity in phenotypes and genotypes, which have rendered gene discovery challenging. The aim of this study was to identify novel genes that underlie pathogenesis of HS patients with CHD. Whole exome sequencing was performed in 25 unrelated HS cases and 100 healthy controls; 19 nonsynonymous variants in 6 novel candidate genes (FLNA, ITGA1, PCNT, KIF7, GLI1, KMT2D) were identified. The functions of candidate genes were further analyzed in zebrafish model by CRISPR/Cas9 technique. Genome-editing was successfully introduced into the gene loci of flna, kmt2d and kif7, but the phenotypes were heterogenous. Disruption of each gene disturbed normal cardiac looping while kif7 knockout had a more prominent effect on liver budding and pitx2 expression. Our results revealed three potential HS pathogenic genes with probably different molecular mechanisms.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping