Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants Article

Full Text via DOI: 10.1056/NEJMoa1200395 PMID: 22970919 Web of Science: 000309406100008
Highly Cited Paper International Collaboration

Cited authors

  • Girirajan, Santhosh; Rosenfeld, Jill A.; Coe, Bradley P.; Parikh, Sumit; Friedman, Neil; Goldstein, Amy; Filipink, Robyn A.; McConnell, Juliann S.; Angle, Brad; Meschino, Wendy S.; Nezarati, Marjan M.; Asamoah, Alexander; Jackson, Kelly E.; Gowans, Gordon C.; Martin, Judith A.; Carmany, Erin P.; Stockton, David W.; Schnur, Rhonda E.; Penney, Lynette S.; Martin, Donna M.; Raskin, Salmo; Leppig, Kathleen; Thiese, Heidi; Smith, Rosemarie; Aberg, Erika; Niyazov, Dmitriy M.; Escobar, Luis F.; El-Khechen, Dima; Johnson, Kisha D.; Lebel, Robert R.; Siefkas, Kiana; Ball, Susie; Shur, Natasha; McGuire, Marianne; Brasington, Campbell K.; Spence, J. Edward; Martin, Laura S.; Clericuzio, Carol; Ballif, Blake C.; Shaffer, Lisa G.; Eichler, Evan E.


  • 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 = 2.11x10(-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.)

Publication date

  • 2012

Published in

International Standard Serial Number (ISSN)

  • 0028-4793

Start page

  • 1321

End page

  • 1331


  • 367


  • 14