Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study

Abstract

Background: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. Methods: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. Results: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. Conclusions: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Clustering of Genetic Anomalies of Cilia Outer Dynein Arm and Central Apparatus in Patients with Transposition of the Great Arteries

“…Intriguingly, a recent WGS analysis showed that abnormalities in cilia-related genes were similar between TGA patients and controls [ 56 ]; in this context, the clustering of several variants in cilia genes could be relevant to identifying susceptibility genotypes that could increase the familiar risk related to cilia defects. Interestingly, a recent report described familial co-segregation of ccTGA and dextro-TGA [ 57 ]. ccTGA has been consistently associated with laterality defects [ 2 , 3 ], and these findings suggest a common pathogenic pathway involving laterality genes in both defects.…”

NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

“…One large class of CHD are those related to laterality defects. Classically the laterality defect classification has included situs inversus totalis (complete mirror-image reversal of the chest and abdominal organs usual positions) and heterotaxy (a state of partial rearrangement or anatomical positioning with regard to the body axes) [ 4 ]. However, both animal and human published studies suggest that other CHD lesions could be due to altered laterality development of the heart [ 4 – 7 ].…”

“…Classically the laterality defect classification has included situs inversus totalis (complete mirror-image reversal of the chest and abdominal organs usual positions) and heterotaxy (a state of partial rearrangement or anatomical positioning with regard to the body axes) [ 4 ]. However, both animal and human published studies suggest that other CHD lesions could be due to altered laterality development of the heart [ 4 – 7 ]. In fact, 3–7% of all apparently isolated CHDs, comprising double outlet right ventricle (DORV), atrioventricular canal defect (AVCD), or transposition of the great arteries (TGA), have been suggested to arise from abnormal embryonic L-R axis patterning [ 5 , 6 ].…”

Genetics of Congenitally Corrected Transposition of the Great Arteries: next generation sequencing shows a mutation load effect for 156 genes involved in cardiac patterning

“…It is most often of sporadic appearance. However, there are some rare familial cases reported in the literature 7 8 . These reported pedigrees suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of CCTGA.…”