title: NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation.
abstract: OBJECTIVE
  Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder.
  
  
  METHODS
  Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed.
  
  
  RESULTS
  Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms-such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication-as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype.
  
  
  CONCLUSIONS
  Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Melanie
authors.initials: M
authors.lastname: Hullings
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Gonzaga-Jauregui
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Loy
authors.forename: Laird G
authors.initials: LG
authors.lastname: Jackson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D004261:DNA Replication; D003635:De Lange Syndrome / Q000235:genetics*; D019066:Facies; D005260:Female; D017353:Gene Deletion; D023061:Gene Order; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D016415:Sequence Alignment
chemical_list: D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins