title: Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.
abstract: BACKGROUND
  Sotos syndrome is characterised by learning difficulties, overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos. In contrast, a recurrent approximately 2 Mb microdeletion has been reported as responsible for approximately 50% of Japanese cases of Sotos.
  
  
  METHODS
  We screened 471 cases for NSD1 mutations and deletions and identified 23 with 5q35 microdeletions. We investigated the deletion size, parent of origin, and mechanism of generation in these and a further 10 cases identified from published reports. We used "in silico" analyses to investigate whether repetitive elements that could generate microdeletions flank NSD1.
  
  
  RESULTS
  Three repetitive elements flanking NSD1, designated REPcen, REPmid, and REPtel, were identified. Up to 18 cases may have the same sized deletion, but at least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In most instances, the microdeletion arose through interchromosomal rearrangements of the paternally inherited chromosome.
  
  
  CONCLUSIONS
  Frequency, size, and mechanism of generation of 5q35 microdeletions differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were identified from a large case series with a broad range of phenotypes, suggesting that sample selection variability is unlikely as a sole explanation for these differences and that variation in genomic architecture might be a contributory factor. Non-allelic homologous recombination between REPcen and REPtel may have generated up to 18 microdeletion cases in our series. However, at least 15 cannot be mediated by these repeats, including at least seven deletions of different sizes, implicating multiple mechanisms in the generation of 5q35 microdeletions.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: K
authors.initials: K
authors.lastname: Tatton-Brown
authors.forename: J
authors.initials: J
authors.lastname: Douglas
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authors.initials: K
authors.lastname: Coleman
authors.forename: G
authors.initials: G
authors.lastname: Baujat
authors.forename: K
authors.initials: K
authors.lastname: Chandler
authors.forename: A
authors.initials: A
authors.lastname: Clarke
authors.forename: A
authors.initials: A
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Davies
authors.forename: F
authors.initials: F
authors.lastname: Faravelli
authors.forename: H
authors.initials: H
authors.lastname: Firth
authors.forename: C
authors.initials: C
authors.lastname: Garrett
authors.forename: H
authors.initials: H
authors.lastname: Hughes
authors.forename: B
authors.initials: B
authors.lastname: Kerr
authors.forename: J
authors.initials: J
authors.lastname: Liebelt
authors.forename: W
authors.initials: W
authors.lastname: Reardon
authors.forename: G B
authors.initials: GB
authors.lastname: Schaefer
authors.forename: M
authors.initials: M
authors.lastname: Splitt
authors.forename: I K
authors.initials: IK
authors.lastname: Temple
authors.forename: D
authors.initials: D
authors.lastname: Waggoner
authors.forename: D D
authors.initials: DD
authors.lastname: Weaver
authors.forename: L
authors.initials: L
authors.lastname: Wilson
authors.forename: T
authors.initials: T
authors.lastname: Cole
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: A
authors.initials: A
authors.lastname: Irrthum
authors.forename: N
authors.initials: N
authors.lastname: Rahman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000483:Alleles; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D006130:Growth Disorders / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007859:Learning Disabilities / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D013577:Syndrome; D020079:Terminal Repeat Sequences
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human