Phenotypic heterogeneity of genomic disorders and rare copy-number variants

Girirajan, S.; Rosenfeld, J. A.; Coe, B. P.; Parikh, S.; Friedman, N.; Goldstein, A.; Filipink, R. A.; McConnell, J. S.; Angle, B.; Meschino, W. S.; Nezarati, M. M.; Asamoah, A.; Jackson, K. E.; Gowans, G. C.; Martin, J. A.; Carmany, E. P.; Stockton, D. W.; Schnur, R. E.; Penney, L. S.; Martin, D. M.; Raskin, S.; Leppig, K.; Thiese, H.; Smith, R.; Aberg, E.; Niyazov, D. M.; Escobar, L. F.; El-Khechen, D.; Johnson, K. D.; Lebel, R. R.; Siefkas, K.; Ball, S.; Shur, N.; McGuire, M.; Brasington, C. K.; Spence, J. E.; Martin, L. S.; Clericuzio, C.; Ballif, B. C.; Shaffer, L. G.; Eichler, E. E.

N Engl J Med. 2012 Sep 14; 367(14):1321-31


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.).

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