title: Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies.
abstract: 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 (IT). The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an 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 ITs underlie ~2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least sixfold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counseling, and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Beata A
authors.initials: BA
authors.lastname: Nowakowska
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Claudia Al
authors.initials: CA
authors.lastname: Ruivenkamp
authors.forename: Birgit
authors.initials: B
authors.lastname: Sikkema-Raddatz
authors.forename: John A
authors.initials: JA
authors.lastname: Crolla
authors.forename: Reinhilde
authors.initials: R
authors.lastname: Thoelen
authors.forename: Marije
authors.initials: M
authors.lastname: Koopmans
authors.forename: Nicolette
authors.initials: N
authors.lastname: den Hollander
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: van der Kevie-Kersemaekers
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Hanneke
authors.initials: H
authors.lastname: Mieloo
authors.forename: Ton
authors.initials: T
authors.lastname: van Essen
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D010375:Pedigree; D014178:Translocation, Genetic