De novo copy number variants associated with intellectual disability have a paternal origin and age bias.

J Med Genet. 2011 Oct 3. [Epub ahead of print]


De novo copy number variants associated with intellectual disability have a paternal origin and age bias.

Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, Pérez-Jurado LA, Veltman JA.

Source1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.



Abstract

BackgroundDe 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.MethodsThis 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.ResultsThe 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).ConclusionThis indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.