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. 2022 Aug;14(8):3008-3015.
doi: 10.21037/jtd-22-970.

Whole exome sequencing identifies novel inherited genetic variants in tetralogy of Fallot

Yu Pan  1 , Manli Liu  1 , Songsong Zhang  1 , Huaxian Mei  1 , Jing Wu  1
Affiliations

Whole exome sequencing identifies novel inherited genetic variants in tetralogy of Fallot

Yu Pan et al. J Thorac Dis. 2022 Aug.

Abstract

Background: Tetralogy of Fallot (TOF) is the most common neonatal cyanotic heart defect, and genetic variation is an important risk factor for the etiology of TOF. Identifying TOF-associated genetic variants is critical to understanding susceptibility and outcome in patients with TOF and may help delineate pathological mechanisms.

Methods: Whole exome sequencing (WES) was performed 19 patients with sporadic TOF and 3 healthy controls. The dbSNP, GnomAD, Denovo-db, and ClinVar databases were used to annotate the mutations. PolyPhen, SIFT, MutationTaster, and FATHMM softwares were used for mutation pathogenicity analysis. Sanger sequencing was used to validate candidate variants.

Results: We identified 21 genetic variants involving 16 genes were found in 12 patients with sporadic TOF. The types of mutations were missense and splicing variants. None of these genes were detected in samples from the 3 healthy controls. These variants include 9 pathogenic variants, 6 suspected pathogenic variants, and 6 variants of unknown significance (VUS). Further analysis showed that the patients with apolipoprotein B (APOB) and ring finger protein 135 (RNF135) variants had more serious clinical symptoms. Sanger sequencing confirmed that the two variants were heterozygous in TOF patients.

Conclusions: We identified several genetic variants associated with TOF and confirmed that RNF135 and ABOB variants were associated with TOF severity. These findings provide new evidence for exploring the genetic mechanism of TOF.

Keywords: APOB; RNF135; Tetralogy of Fallot (TOF); genetic variants; whole-genome sequencing (WES).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-970/coif). YP reports that this study was supported by the Guizhou Science and Technology Support Program (Guizhou Science and Technology Cooperation Support 2018-2783) and the National Natural Science Foundation of China (No. 81860273). The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Sanger sequencing of APOB and RN135 variations. (A) The sequence of APOB wild type; (B) the sequence of APOB NM_000384.3:c.10700C>T; (C) the sequence of RNF135 wild type; (D) the sequence of RNF135 NM_032322.4:c.1015del. Blue arrow indicates wild-type allele, red arrow indicates mutant allele. APOB, apolipoprotein B; RNF135, ring finger protein 135.
See this image and copyright information in PMC

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