Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies

Joris Robert Vermeesch (1) , Beata A Nowakowska (1) , Nicole de Leeuw (1) , Claudia Ruivenkamp (1) , Birgit Sikkema-Raddatz (1) , John A Crolla (1) , Reinhilde Thoelen (1) , Marije Koopmans (1) , Nicolettè den Hollander (1) , Arie van Haeringen (1) , Anne-Marie van Der Kevie-Kersemaekers (1) , Rolph Pfundt (1) , Hanneke Mieloo (1) , Ton van Essen (1) , Bert Ba de Vries (1) , Andrew J Green (1) , Willie Reardon (1) , Jean-Pierre Fryns (1)

1 Department of Human Genetics

In several laboratories, genome wide array analysis has been implemented as the first tier diagnostic test for the identification of copy number changes in patients with mental retardation and/or congenital anomalies. The identification of a pathogenic copy number variant (CNV) is not only important to make a proper diagnosis but also to enable the accurate estimation of the recurrence risk to family members. Upon the identification of a de novo interstitial loss or gain the risk recurrence is considered very low. However, this risk is 50% if one of the parents is carrier of a balanced insertional translocation. The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an insertional translocation (IT). To determine the frequency with which insertional balanced translocations would be the origin of submicroscopic imbalances, we investigated the potential presence of an IT in a consecutive series of 477 interstitial CNVs, in which the parental origin has been tested by FISH, among 14 293 patients with developmental abnormalities referred for array. We demonstrate that insertional translocations underlie approximately 2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least 6 fold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counselling and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.

Mots clés: insertional translocation; interstitial aberrations; structural chromosomal rearrangements

Domaines: Génétique

Joris Robert Vermeesch, Beata A Nowakowska, Nicole de Leeuw, Claudia Ruivenkamp, Birgit Sikkema-Raddatz, et al.. Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.157⟩. ⟨hal-00678797⟩