Movement Abnormalities in Children with 16p11.2 Deletion or Duplication and Their Association with ASD and Other Neurodevelopmental Challenges

Background: Motor abnormalities not identified by the traditional neurologic examination are seen with increased prevalence in autism spectrum disorders (ASD) and other neurodevelopmental disabilities (NDDs) not typically defined by their motor deficits, including speech and language disorders, attention-deficit hyperactivity disorder, and intellectual disability. Important insights into the neurobiological bases of NDDs can be obtained by examining the relationship between motor and cognitive function, but are complicated by the heterogeneity of NDD populations. The Simons Variations in Individuals Project is a research endeavor taking a “genetics-first” approach to studying a large cohort of individuals with 16p11.2 deletions (del) and duplications (dup) – recurrent copy-number variants (CNVs) that increase the risk of ASD and other NDDs – without regard to prior clinical behavioral/developmental diagnosis.

Objectives: To examine (1) if these genetically-identified populations have measureable motor problems not identified by traditional neurologic exam; (2) if such deficits are associated with ASD and ASD symptoms; intellectual disability; neurologic abnormalities; or other behavioral diagnoses seen in these populations; and (3) if the degree of motor deficit seen in these two populations differ independent of other identified neurodevelopmental factors.

Methods: The Movement Assessment Battery for Children – 2 was administered to 82 children with 16p11.2 del (n=49) or dup (n=33). One-sample t-tests were used to compare total standardized z-scores (MABC-T) in the del or dup groups to the general population and two-sample t-tests were used to compare MABC-T between del and dup patients. Two-sample t-tests and Pearson’s correlation were used to assess for associations between MABC-T and various neurodevelopmental factors in del or dup groups. Multivariable linear regression models were used to examine the independent associations of MABC-T with neurodevelopmental factors while controlling for FSIQ, ASD, and the presence of dup vs del.

Results: Del and dup groups each exhibited low MABC-T compared to norm (-2.1 SD and -1.7 SD, each p<0.001; del versus dup: p<0.001). Higher Autism Diagnostic Observation Schedule-Calibrated Severity Score (ADOS-CSS) was associated with lower MABC-T in both groups (del: r=-0.5, p=0.001; dup: r=-0.4, p=0.03), while diagnosis of ASD was only associated with worse MABC-T in del patients (p<0.005). In del, lower MABC-T was also associated with symptoms of appendicular weakness (p=0.04). In dup patients, lower MABC-T was also associated with lower FSIQ (r=0.6, p<0.001), articulation disorder (p=0.01),  and hypotonia symptoms (p=0.03) and (truncal) signs (p<0.001). Neither language disorder nor ADHD were associated with MABC-T. FSIQ, ASD diagnosis, hypotonia (symptoms or signs), and the presence of dup (versus del) were all independently associated with lower MABC-T (all p≤0.04). ADOS-CSS was also an independent predictor of lower MABC-T when adjusting for FSIQ, ASD, and CNV, while diagnosis of articulation disorder did not survive adjustment for FSIQ and CNV.

Conclusions:  Children with 16p11.2 del and dup have quantifiable movement deficits associated with multiple independent factors. There are differential associations of deficits with physical and cognitive abnormalities in del versus dup, as well as an independent association of motor deficits with presence of dup versus del.