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Copy number variants (CNVs) are thought to underlie many human developmental abnormalities. However, it is unclear how many of these CNVs exert their pathogenic effects or, in particular, how distinct CNVs at dispersed loci can give rise to the same abnormality. We hypothesize that the mouse orthologs of genes whose copy number change gives rise to the same human abnormality might also yield a similar phenotype when disrupted in mice. Thus, by bringing together a large number of disparate CNVs, we may be able to identify an unusually overrepresented phenotype among the affected genes' mouse orthologs. We obtained 1,624 de novo CNVs identified in patients with developmental abnormalities from Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources and European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations database. Forming CNV sets for each of 1,088 distinct human abnormalities, we were able to associate a total of 143 (13%) human abnormalities with mouse model phenotypes. Although many mouse phenotypes are readily comparable to their associated human abnormality, others are less so, generating novel biological hypotheses. Of the 2,086 candidate genes that contribute to these associations, 65% have not been previously associated with human disease in Online Mendelian Inheritance in Man, and their distribution suggests both extensive pleiotropy and epistasis while also proposing a small number of simple additive consequences.

Original publication




Journal article


Hum Mutat

Publication Date





874 - 883


Animals, Congenital Abnormalities, DNA Copy Number Variations, Disease Models, Animal, Epistasis, Genetic, Genetic Association Studies, Genetic Pleiotropy, Growth Disorders, Humans, Mice, Phenotype