The clinical significance of small copy number variants in neurodevelopmental disorders

Reza Asadollahi, Beatrice Oneda, Pascal Joset, Silvia Azzarello-Burri, Deborah Bartholdi, Katharina Steindl, Marie Vincent, Joana Cobilanschi, Heinrich Sticht, Rosa Baldinger, Regina Reissmann, Irene Sudholt, Christian T Thiel, Arif B Ekici, André Reis, Emilia K Bijlsma, Joris Andrieux, Anne Dieux, David FitzPatrick, Susanne RitterAlessandra Baumer, Beatrice Latal, Barbara Plecko, Oskar G Jenni, Anita Rauch

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)677-88
Number of pages12
JournalJournal of Medical Genetics
Issue number10
Publication statusPublished - Oct 2014


Dive into the research topics of 'The clinical significance of small copy number variants in neurodevelopmental disorders'. Together they form a unique fingerprint.

Cite this