Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents

Recurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking. Here we perform array-based CNV calling in 12,252 mother-father-child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions. We estimate the total prevalence of recurrent NDD CNVs (duplications and deletions) in live-born children to 0.48% (95% C.I.: 0.37-0.62%), i.e., similar to 1 in 200 newborns has either a deletion or duplication in these NDDs associated regions. Approximately a third of the newborn recurrent NDD CNVs (34%,N = 20/59) are de novo variants. We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (similar to 1:2000), 15q11.2 duplications (similar to 1:4000), 15q13.3 microdeletions (similar to 1:2500), 16p11.2 proximal microdeletions (similar to 1:2000) and 17q12 deletions (similar to 1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (similar to 1:12,000). In conclusion, our analysis of an unselected and representative population of newborns and their parents provides a clearer picture of the rate of recurrent microdeletions/duplications implicated in neurodevelopmental delay. These results will provide an important resource for genetic diagnostics and counseling.

Automated summary

The study analyzed the inheritance patterns of 26 recurrent NDD CNVs in 13 genomic regions in 12,252 mother-father-child trios from the Norwegian Mother, Father, and Child Cohort Study. The total prevalence of recurrent NDD CNVs in live-born children was estimated to be 0.48%, with approximately a third being de novo variants. The prevalence of different NDD CNVs varied, highlighting the importance of the results for genetic diagnostics and counseling.