Circ Genom Precis Med. 2022 Jun;15(3):e003464. doi: 10.1161/CIRCGEN.121.003464. Epub 2022 May 12.
Marine Tortigue 1 2 3, Lynne E Nield 4, Matilde Karakachoff 5, Christopher J McLeod 6, Emre Belli 7, Sonya V Babu-Narayan 8, Solène Prigent 2 3, Angèle Boet 7, Miriam Conway 8, Robert W Elder 9, Magalie Ladouceur 10, Paul Khairy 11, Ewa Kowalik 12, David M Kalfa 13, David J Barron 4, Shafi Mussa 14, Anita Hiippala 15, Joel Temple 16, Sylvia Abadir 11 17, Laurianne Le Gloan 1 18, Matthias Lachaud 19, Shubhayan Sanatani 20, Jean-Benoit Thambo 21, Céline Grunenwald Gronier 2 3, Pascal Amedro 21 22, Guy Vaksmann 23, Anne Charbonneau 24, Linda Koutbi 25, Caroline Ovaert 26 27, Ali Houeijeh 28, Nicolas Combes 7 29, Philippe Maury 30, Guillaume Duthoit 31, Bérengère Hiel 32, Christopher C Erickson 33, Caroline Bonnet 34, George F Van Hare 35, Christian Dina 1, Clément Karsenty 36 37, Emmanuelle Fournier 7, Mathieu Le Bloa 38, Robert H Pass 39, Leonardo Liberman 13, Juha-Matti Happonen 15, James C Perry 40, Bénédicte Romefort 2, Nadir Benbrik 2, Quentin Hauet 2, Alain Fraisse 8, Michael A Gatzoulis 8, Dominic J Abrams 41, Anne M Dubin 42, Siew Yen Ho 8, Richard Redon 1 43, Emile A Bacha 13, Jean-Jacques Schott 1 43, Alban-Elouen Baruteau 1 2 3 43
PMID: 35549293 DOI: 10.1161/CIRCGEN.121.003464
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.
Keywords: aorta; arteries; heterotaxy syndrome; mitral valve; rare disease.