Background: 16p11.2 deletion syndrome (16p11.2 DS, BP4-BP5) is a recurrent CNV that occurs de novo in approximately 70% of cases and confers risk for neurodevelopmental disorders (NDD), including intellectual disability (ID) and autism spectrum disorders (ASD). This study focusses on presenting symptoms, developmental milestones and cognitive trajectories.

Methods: Digital medical records, in-person assessments and parental interviews on medical and developmental history of 23 children (5-16 years, 12/16 de novo) with a confirmed BP4-BP5 16p11.2 DS diagnosed and followed up at the Center for Human Genetics UZ Leuven were reviewed and analysed. Standardised intelligence tests (WISC-V NL) were administered in all, and longitudinal IQ-data were available in a subgroup (83%,19/23).

Results: Most prominent clinical issues were nutritional problems (68%,15/22), transient or permanent hearing impairment (52%,12/23), overweight (50%,10/20) and epilepsy or seizures (43%,10/23). Developmental milestones were delayed across several developmental domains (motor, language). At least one neurodevelopmental disorder (NDD) was diagnosed in 74% (17/23), most commonly ASD (48%, 11/23) and developmental coordination disorder (DCD: 36%, 8/23). Average IQ was in the mild ID range (IQ 69.2; SD: 12.7; range 45-91) with 39% having borderline IQ (IQ 70-84). Longitudinal IQ-data with first assessment at a median age of 5y10m and second timepoint at a median age of 10y10m, indicate that children with 16p11.2 DS perform statistically significantly lower on the second timepoint (p<0.001) with 53% (10/19) showing a growing into deficit trajectory.

Conclusion: Delayed motor and language milestones are frequent in 16p11.2 DS carriers (BP4-BP5), as well as medical issues such as feeding problems, overweight and epilepsy. School-aged children with 16p11.2 DS show increasing learning and cognitive impairments over time and present with high rates of NDD (ASD, DCD). Future studies in larger cohorts including carrier relatives are needed to gain more insight into the penetrance and phenotypic variability of 16p11.2 DS.

Keywords: 16p11.2 deletion syndrome, copy number variants, early development, developmental trajectories, deep phenotyping