Abstract
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., ~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 (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~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.
Highlights
These authors contributed : Dinka Smajlagić, Ksenia Lavrichenko
In this study we investigated recurrent copy number variations (CNVs) that span chromosomal regions known to be associated with neurodevelopmental disorders (NDDs) i.e., 1q21.1, 3q29, 7q11.23, 15q11.2–13.1, 15q13.3, 16p11.2 distal and proximal, 17p13.3, 17p11.2, 17q12, 17q21.31 and 22q11.2 distal and proximal (Supplementary File 3)
After classification of CNVs and quality control (QC), 59 recurrent NDD CNVs were observed in the offspring (Supplementary File 2), of which 39 were identified as inherited and 20 were identified as de novo variants (Table 1, Fig. 1)
Summary
Recurrent CNVs have been implicated in a range of rare genomic disorders and neurodevelopmental traits, e.g., 1q21.1 microdeletion- and Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway. High participation rate, relatively low ascertainment bias, and the child–parent trio (i.e., mother–father–child) design together with large sample size make MoBa a unique resource for improving our understanding of the population prevalence and inheritance pattern for these recurrent CNVs. In this study, we performed CNV analysis in 12,252 MoBa trios and provide comprehensive analyses of the prevalence, inheritance pattern and de novo rate of recurrent copy number deletions and duplications implicated in neurodevelopmental genomic disorders, i.e., microdeletions and microduplications in the 1q21.1, 3q29, 7q11.23 (Williams-Beuren syndrome), 15q11.2 (Prader–Willi/Angelman syndrome (PW/AS)), 15q13.3, 16p11.2 distal and proximal, 17p13.3 (Miller-Dieker syndrome), 17p11.2 (Smith-Magenis and Potocki-Lupski syndrome), 17q12, 17q21.31 (Koolen-de Vries syndrome), and 22q11.2 distal and proximal regions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
