Nicole Hoppman-Chaney and Jin Sung Jang contributed equally to the work.
Article first published online: 21 NOV 2011
Copyright © 2011 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 1, pages 193–198, January 2012
How to Cite
Hoppman-Chaney, N., Jang, J. S., Jen, J., Babovic-Vuksanovic, D. and Hodge, J. C. (2012), In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome. Am. J. Med. Genet., 158A: 193–198. doi: 10.1002/ajmg.a.34360
How to cite this article: Hoppman-Chaney N, Jang JS, Jen J, Babovic-Vuksanovic D, Hodge JC. 2012. In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome. Am J Med Genet Part A 158A:193–198.
- Issue published online: 19 DEC 2011
- Article first published online: 21 NOV 2011
- Manuscript Accepted: 2 OCT 2011
- Manuscript Received: 14 JUL 2011
- Cornelia de Lange Syndrome;
- dominant negative;
- Turner syndrome;
- multi-exon deletion
Cornelia de Lange Syndrome (CdLS) is a genetically heterogeneous disorder characterized by dysmorphic facial features, cleft palate, limb defects, growth retardation, and developmental delay. Approximately 60% of patients with CdLS have an identifiable mutation in the NIPBL gene at 5p13.2. Recently, an X-linked form of CdLS with a generally milder phenotype was attributed to mutation of the structural maintenance of chromosomes 1A gene (SMC1A) at Xp11.22. Relatively few CdLS patients with mutations in SMC1A are known; female carriers have minor facial dysmorphism and cognitive deficiency without major structural abnormalities. To date, all mutations identified in SMC1A are missense or small in-frame deletions that preserve the open reading frame of the gene and likely have a dominant-negative effect. We report on a female with monosomy X mosaicism and a phenotype suggestive of a severe form of CdLS who presented with growth and mental retardation, multiple congenital anomalies, and facial dysmorphism. Array CGH confirmed mosaic monosomy X and identified a novel deletion of SMC1A spanning multiple exons, suggesting a possible loss-of-function effect. Sequencing of both genomic and cDNA demonstrated an 8,152 bp deletion of genomic DNA from exon 13 to intron 16. Although a loss-of-function effect cannot be excluded, the resulting mRNA remains in-frame and is expressed in peripheral blood lymphocytes, suggesting a dominant-negative effect. We hypothesize that the size of this deletion compared to previously reported mutations may account for this patient's severe CdLS phenotype. The presence of mosaic monosomy X may also modify the phenotype. © 2011 Wiley Periodicals, Inc.