In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome

Nicole Hoppman-Chaney, Jin Sung Jang, Jin Jen, Dusica Babovic-Vuksanovic, Jennelle C. Hodge

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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 8,152bp 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.

Original languageEnglish (US)
Pages (from-to)193-198
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number1
StatePublished - Jan 2012


  • Cornelia de Lange Syndrome
  • Dominant negative
  • Multi-exon deletion
  • SMC1A
  • Turner syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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