title: Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome.
abstract: BACKGROUND
  Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.
  
  
  METHODS
  We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).
  
  
  RESULTS
  Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.
  
  
  CONCLUSIONS
  Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.
authors.affiliation: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.forename: Chiara
authors.initials: C
authors.lastname: Picinelli
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.forename: Daniela
authors.initials: D
authors.lastname: Rusconi
authors.forename: Maura
authors.initials: M
authors.lastname: Masciadri
authors.forename: Anna
authors.initials: A
authors.lastname: Cereda
authors.forename: Cinzia
authors.initials: C
authors.lastname: Marzocchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.forename: Palma
authors.initials: P
authors.lastname: Finelli
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D002894:Chromosomes, Human, Pair 4; D056915:DNA Copy Number Variations; D003635:De Lange Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D042822:Genomic Instability; D006801:Humans; D008297:Male; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D014178:Translocation, Genetic; D055815:Young Adult; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D000098550:Structural Maintenance of Chromosome Protein 1
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