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

Circ Genom Precis Med. 2022 Jun;15(3):e003464. doi: 10.1161/CIRCGEN.121.003464. Epub 2022 May 12.


Marine Tortigue 1 2 3Lynne E Nield 4Matilde Karakachoff 5Christopher J McLeod 6Emre Belli 7Sonya V Babu-Narayan 8Solène Prigent 2 3Angèle Boet 7Miriam Conway 8Robert W Elder 9Magalie Ladouceur 10Paul Khairy 11Ewa Kowalik 12David M Kalfa 13David J Barron 4Shafi Mussa 14Anita Hiippala 15Joel Temple 16Sylvia Abadir 11 17Laurianne Le Gloan 1 18Matthias Lachaud 19Shubhayan Sanatani 20Jean-Benoit Thambo 21Céline Grunenwald Gronier 2 3Pascal Amedro 21 22Guy Vaksmann 23Anne Charbonneau 24Linda Koutbi 25Caroline Ovaert 26 27Ali Houeijeh 28Nicolas Combes 7 29Philippe Maury 30Guillaume Duthoit 31Bérengère Hiel 32Christopher C Erickson 33Caroline Bonnet 34George F Van Hare 35Christian Dina 1Clément Karsenty 36 37Emmanuelle Fournier 7Mathieu Le Bloa 38Robert H Pass 39Leonardo Liberman 13Juha-Matti Happonen 15James C Perry 40Bénédicte Romefort 2Nadir Benbrik 2Quentin Hauet 2Alain Fraisse 8Michael A Gatzoulis 8Dominic J Abrams 41Anne M Dubin 42Siew Yen Ho 8Richard Redon 1 43Emile A Bacha 13Jean-Jacques Schott 1 43Alban-Elouen Baruteau 1 2 3 43

PMID: 35549293 DOI: 10.1161/CIRCGEN.121.003464



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.

Keywords: aorta; arteries; heterotaxy syndrome; mitral valve; rare disease.

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