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N Engl J Med. 2012 Oct 4;367(14):1321-31. doi: 10.1056/NEJMoa1200395. Epub 2012 Sep 12.

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

Author information

  • 1Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

Erratum in

  • N Engl J Med. 2012 Dec 13;367(24):2362.

Abstract

BACKGROUND:

Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.

METHODS:

We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.

RESULTS:

Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02).

CONCLUSIONS:

Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

Comment in

PMID:
22970919
[PubMed - indexed for MEDLINE]
PMCID:
PMC3494411
Free PMC Article

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