19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression
Article first published online: 19 JAN 2011
© 2011 John Wiley & Sons A/S
Volume 81, Issue 1, pages 56–63, January 2012
How to Cite
Lehman, A., du Souich, C., Chai, D., Eydoux, P., Huang, J., Fok, A., Avila, L., Swingland, J., Delaney, A., McGillivray, B., Goldowitz, D., Argiropoulos, B., Kobor, M. and Boerkoel, C. (2012), 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression. Clinical Genetics, 81: 56–63. doi: 10.1111/j.1399-0004.2010.01615.x
- Issue published online: 12 DEC 2011
- Article first published online: 19 JAN 2011
- Accepted manuscript online: 13 DEC 2010 07:36AM EST
- Received 13 September 2010, revised and accepted for publication 9 December 2010
- copy number variant;
- genomic disorder;
- intellectual disability;
- Sotos syndrome
Lehman AM, du Souich C, Chai D, Eydoux P, Huang JL, Fok AK, Avila L, Swingland J, Delaney AD, McGillivray B, Goldowitz D, Argiropoulos B, Kobor MS, Boerkoel CF. 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.
Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.