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 journalArticle

Abstract

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
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

De Lange Syndrome
Exons
Chromosomes
Maintenance
Turner Syndrome
Mutation
Genes
Phenotype
Mosaicism
Cleft Palate
Growth
Intellectual Disability
Introns
Open Reading Frames
Extremities
Complementary DNA
Lymphocytes
Messenger RNA
DNA

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome. / Hoppman-Chaney, Nicole; Jang, Jin Sung; Jen, Jin; Babovic-Vuksanovic, Dusica; Hodge, Jennelle C.

In: American Journal of Medical Genetics, Part A, Vol. 158 A, No. 1, 01.2012, p. 193-198.

Research output: Contribution to journalArticle

Hoppman-Chaney, Nicole ; Jang, Jin Sung ; Jen, Jin ; Babovic-Vuksanovic, Dusica ; Hodge, Jennelle C. / In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome. In: American Journal of Medical Genetics, Part A. 2012 ; Vol. 158 A, No. 1. pp. 193-198.
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