title: Copy number variants on the X chromosome in women with primary ovarian insufficiency.
abstract: OBJECTIVE
  To investigate whether submicroscopic copy number variants (CNVs) on the X chromosome can be identified in women with primary ovarian insufficiency (POI), defined as spontaneous secondary amenorrhea before 40 years of age accompanied by follicle-stimulating hormone levels above 40 IU/L on at least two occasions.
  
  
  METHODS
  Analysis of intensity data of single nucleotide polymorphism (SNP) probes generated by genomewide Illumina 370k CNV BeadChips, followed by the validation of identified loci using a custom designed ultra-high-density comparative genomic hybridization array containing 48,325 probes evenly distributed over the X chromosome.
  
  
  METHODS
  Multicenter genetic cohort study in the Netherlands.
  
  
  METHODS
  108 Dutch Caucasian women with POI, 97 of whom passed quality control, who had a normal karyogram and absent fragile X premutation, and 235 healthy Dutch Caucasian women as controls.
  
  
  METHODS
  None.
  
  
  METHODS
  Amount and locus of X chromosomal microdeletions or duplications.
  
  
  RESULTS
  Intensity differences between SNP probes identify microdeletions and duplications. The initial analysis identified an overrepresentation of deletions in POI patients. Moreover, CNVs in two genes on the Xq21.3 locus (i.e., PCDH11X and TGIF2LX) were statistically significantly associated with the POI phenotype. Mean size of identified CNVs was 262 kb. However, in the validation study the identified putative Xq21.3 deletions samples did not show deviations in intensities in consecutive probes.
  
  
  CONCLUSIONS
  X chromosomal submicroscopic CNVs do not play a major role in Caucasian POI patients. We provide guidelines on how submicroscopic cytogenetic POI research should be conducted.
authors.affiliation: Department of Reproductive Medicine and Gynecology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. knauff@gmail.com
authors.forename: Erik A H
authors.initials: EA
authors.lastname: Knauff
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Peter L
authors.initials: PL
authors.lastname: Pearson
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouchard
authors.forename: Bart C J M
authors.initials: BC
authors.lastname: Fauser
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D054928:Validation Studies as Topic