title: Clinical significance of de novo and inherited copy-number variation.
abstract: Copy-number variations (CNVs) are a common cause of intellectual disability and/or multiple congenital anomalies (ID/MCA). However, the clinical interpretation of CNVs remains challenging, especially for inherited CNVs. Well-phenotyped patients (5,531) with ID/MCA were screened for rare CNVs using a 250K single-nucleotide polymorphism array platform in order to improve the understanding of the contribution of CNVs to a patients phenotype. We detected 1,663 rare CNVs in 1,388 patients (25.1%; range 0-5 per patient) of which 437 occurred de novo and 638 were inherited. The detected CNVs were analyzed for various characteristics, gene content, and genotype-phenotype correlations. Patients with severe phenotypes, including organ malformations, had more de novo CNVs (P < 0.001), whereas patient groups with milder phenotypes, such as facial dysmorphisms, were enriched for both de novo and inherited CNVs (P < 0.001), indicating that not only de novo but also inherited CNVs can be associated with a clinically relevant phenotype. Moreover, patients with multiple CNVs presented with a more severe phenotype than patients with a single CNV (P < 0.001), pointing to a combinatorial effect of the additional CNVs. In addition, we identified 20 de novo single-gene CNVs that directly indicate novel genes for ID/MCA, including ZFHX4, ANKH, DLG2, MPP7, CEP89, TRIO, ASTN2, and PIK3C3.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.forename: Stephen
authors.initials: S
authors.lastname: Meader
authors.forename: Claudia J M
authors.initials: CJ
authors.lastname: Hellebrekers
authors.forename: Ilse J M
authors.initials: IJ
authors.lastname: Thoonen
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
keywords: CNV; SNP; copy number variation; genotype-phenotype; human phenotype ontology