Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries

Abstract

Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. Objective: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. Methods and Results: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease–causing genes, such as FOXH1 , were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

Mutations in RNA Methyltransferase Gene NSUN5 Confer High Risk of Outflow Tract Malformation

“…In our study, all the predicted deleterious NSUN5 mutations in TOF patients were heterozygous. A recent study reported that a 33% transposition of the great arteries, a type of OFT defect, had more than one candidate gene hit by putative heterozygous deleterious variants and that the cases might have been affected by polygenic inheritance (Liu et al, 2020). Such an inheritance pattern might account for the findings of our genetic analyses of TOF patients.…”

Summix: A method for detecting and adjusting for population structure in genetic summary data

“…Studies have used gnomAD as either the primary or secondary external control sample. While many of these studies are in European [39][40][41] or East Asian 42,43 ancestral groups, which we find to contain little to no other continental reference ancestry, some studies use gnomAD groups that contain admixture (e.g., African/African American, American/Latinx, and South Asian) for comparison without adjusting population structure. 6,16,44 We evaluate the potential utility of Summix's ancestryadjusted AF by producing ancestry-adjusted AFs for Clin-Var variants, for the CF variant p.Phe508del in CFTR, and for a case-control analysis of PADI3, a gene where gno-mAD was used as an external control sample to identify as-sociation with central centrifugal cicatricial alopecia in women with African ancestry.…”

Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries

“…Though this evidence seems to suggest a possible link between RYR1 variants and conotruncal heart defects, further evidence supporting the link runs short. In a large study of 66 family trios with a phenotype of d‐TGA, none were found to have RYR1 variants on whole‐exome sequencing (Liu et al, 2020 ). This study had limited sensitivity for intronic variants though, a possible limitation.…”