Journal Article

Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice

Zweier, Christiane, Price, Sue, Stewart, Helen, Moreau, Clara, Raynaud, Martine, Barnicoat, Angela, Hjalgrim, Helle, Gregersen, Pernille Axel, Till, Marianne, Ousager, Lilian Bomme, Nizon, Mathilde, Ville, Dorothée, Pierquin, Genevieve, Rossi, Massimiliano, Passeggeri, Marzia, Blanchet, Patricia, Møller, Rikke Steensbjerre, Trakadis, Yannis, Douard, Elise, Krumbiegel, Mandy, Ramaekers, Vincent, Bütschi, Florence Niel, Wilkie, Andrew, Sanlaville, Damien, Geneviève, David, Van Dijck, Anke, Hüffmeier, Ulrike, Mitchell, Grant, Reis, André, Theil, Christian T, Ferrarini, Alessandra, Mortemousque, Isabelle, Sørensen, Kristina Pilekær, Skytte, Anne-Bine, Michaud, Jacques, Vonwill, Sandrine, Jønch, Aia Elise, Lespinasse, James, Campbell, Carolyn, Fellmann, Florence, Chelloug, Nora, Svaneby, Dea, Le Caignec, Cédric, Puechberty, Jacques, Lefroy, Henrietta, Andrieux, Joris, Lesca, Gaetan, Richetin, Sonia, Isidor, Bertrand, Sarda, Pierre, Stanzial, Franco, Jacquemont, Sébastien, Kini, Usha, Brasch-Andersen, Charlotte, Bojesen, Anders, Kjelgaard, Ditte, Mercier, Sandra, Hoyer, Juliane, Wiessner, Antje, Pain, Aurel

2019

Overview

BackgroundThe 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.MethodsWe performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.ResultsThe deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.ConclusionsWe recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: 15q11.2 copy-number variants / Autism / Autistic Disorder - genetics / Cardiovascular disease / Case-Control Studies / Cognitive ability / Cohort Studies / Congenital diseases / congenital heart disease / Copy-Number Variation / DNA Copy Number Variations / Epilepsy / Epilepsy - genetics / Estimates / Female / Genetic counseling / Genetic variability / Genetics / Genetics & genetic processes / Génétique & processus génétiques / Heart Diseases - congenital / Heart Diseases - genetics / Human health and pathology / Humans / Intellectual disabilities / Intellectual Disability - genetics / Laboratories / Life Sciences / Loss of Function Mutation / loss-of-function intolerance / Male / Mathematical models / Mental disorders / Mutation / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Phenotypic variations / Schizophrenia / Sciences du vivant / Sequence Deletion / Statistical analysis / Studies / Systematic review