title: De novo copy number variants associated with intellectual disability have a paternal origin and age bias.
abstract: BACKGROUND
  De novo mutations and structural rearrangements are a common cause of intellectual disability (ID) and other disorders with reduced or null reproductive fitness. Insight into the genomic and environmental factors predisposing to the generation of these de novo events is therefore of significant clinical importance.
  
  
  METHODS
  This study used information from single nucleotide polymorphism microarrays to determine the parent-of-origin of 118 rare de novo copy number variations (CNVs) detected in a cohort of 3443 patients with ID.
  
  
  RESULTS
  The large majority of these CNVs (76%, p=1.14×10(-8)) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02).
  
  
  CONCLUSIONS
  This indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. j.hehir@antrg.umcn.nl
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: Benjamín
authors.initials: B
authors.lastname: Rodríguez-Santiago
authors.forename: Lisenka E
authors.initials: LE
authors.lastname: Vissers
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D009426:Netherlands; D020411:Oligonucleotide Array Sequence Analysis; D010331:Paternal Age; D020641:Polymorphism, Single Nucleotide; D056916:Segmental Duplications, Genomic; D012737:Sex Factors; D013091:Spermatogenesis