title: In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome.
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 8,152 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.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Nicole
authors: N
authors: Hoppman-Chaney
authors: Jin Sung
authors: JS
authors: Jang
authors: Jin
authors: J
authors: Jen
authors: Dusica
authors: D
authors: Babovic-Vuksanovic
authors: Jennelle C
authors: JC
authors: Hodge
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D003635:De Lange Syndrome / Q000235:genetics*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D012333:RNA, Messenger; D000098550:Structural Maintenance of Chromosome Protein 1