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

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.

Fig. 1. Circular plot of recurrent CNVs implicated in NDDs identified in MoBa trios.

The tracks from outer to inner circles: ANN (annotation); DATA (our data): (1) ANN:Chromosomes  on an ideogram; (2) ANN:NDD-relevant reference intervals; (3) DATA:de novo deletions; (4) DATA:de novo duplications; (5) DATA:inherited deletions; (6) DATA:inherited duplications; (7) ANN:genes of interest; (8) ANN:ClinGen Benign Loss cumulative track; (9) ANN:ClinGen Benign Gain cumulative track; (10) ANN:ClinGen Pathogenic Loss cumulative track; (11) ANN:ClinGen Pathogenic Gain cumulative track.

Fig. 2. Parental origin of recurrent CNVs implicated in NDDs identified in MoBa trios.

The total number of NDD CNVs with resolved parent-of-origin is 58 (for a single de novo duplication in 16p11.2 distal region it was not possible to resolve the inheritance status).

Fig. 3. Transmission of recurrent CNVs implicated in NDDs identified in MoBa.

Parents label indicates number of CNVs stratified on parental status, transmitted label indicates number of transmitted NDD CNVs. Mat maternal origin, Pat paternal origin, * indicates P values from transmission disequilibrium test with one degree of freedom.