TY - JOUR T1 - The clinical significance of small copy number variants in neurodevelopmental disorders JF - Journal of Medical Genetics JO - J Med Genet SP - 677 LP - 688 DO - 10.1136/jmedgenet-2014-102588 VL - 51 IS - 10 AU - Reza Asadollahi AU - Beatrice Oneda AU - Pascal Joset AU - Silvia Azzarello-Burri AU - Deborah Bartholdi AU - Katharina Steindl AU - Marie Vincent AU - Joana Cobilanschi AU - Heinrich Sticht AU - Rosa Baldinger AU - Regina Reissmann AU - Irene Sudholt AU - Christian T Thiel AU - Arif B Ekici AU - André Reis AU - Emilia K Bijlsma AU - Joris Andrieux AU - Anne Dieux AU - David FitzPatrick AU - Susanne Ritter AU - Alessandra Baumer AU - Beatrice Latal AU - Barbara Plecko AU - Oskar G Jenni AU - Anita Rauch Y1 - 2014/10/01 UR - http://jmg.bmj.com/content/51/10/677.abstract N2 - Background Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. Methods By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs. Results We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. Conclusions These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions. ER -