Clinical significance of de novo and inherited copy-number variation

Hum Mutat. 2013 Dec;34(12):1679-87. doi: 10.1002/humu.22442. Epub 2013 Oct 10.


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.

Keywords: CNV; SNP; copy number variation; genotype-phenotype; human phenotype ontology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Computational Biology / methods
  • DNA Copy Number Variations*
  • Female
  • Genetic Association Studies*
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide