Neurological Abnormalities Among 16p11.2 Deletion and Duplication Carriers

Background: Deletions and duplications of 16p11.2 (del and dup 16p) are recurrent genetic variations recently found to increase the risk of autism spectrum and other neurodevelopmental disorders. While some small studies have identified neurologic abnormalities in individuals with del and dup 16p, the nature and prevalence of neurologic exam abnormalities have not been well-established in large cohorts.

Objectives: To characterize the neurological findings seen in a large cohort of individuals with deletions or duplications of 16p11.2 from the Simons Variation in Individuals Project.

Methods: We performed neurologic examinations (including assessment for spinal and neurocutaneous abnormalities) on deletion carriers (del; n=69) and duplication carriers (dup; n=61) to define the range of findings in these groups. We used one-sample t-tests to assess whether head circumference (z-score for age) in each group differed significantly from the general population. Fisher’s exact tests were used to assess for differences in frequency of individual neurologic exam findings between age groups: children (<11 years old), adolescents (11–17 years old) and adults (≥18 years old). Data collection and analysis are ongoing and presentation of findings will also examine the association of neurologic exam findings with autism spectrum disorder symptoms and cognitive abilities.

Results: Mean (±SD) age in months was 120±96 for del (48 children, 18 adolescents, 3 adults) and 224±207 for dup (33 children, 4 adolescents, and 24 adults). Head circumference z-scores for age were large for del (1.3±1.0; p<0.0001) and average for dup (–0.19±1.17; p=0.3). Abnormalities of speech articulation (del 81%, dup 24%), deep tendon reflexes (61%, 49%), appendicular tone (58%, 47%), and casual gait (36%, 27%) were prominent among both groups. Both groups also exhibited spinal curvature abnormalities (40%, 24%), sacral dimples (30%, 24%), and numerous but varied neurocutaneous findings (50%, 51%). Less common findings included facial tone and strength abnormalities (del 16%, dup 7%), truncal hypotonia (13%, 12%), and dysrhythmia (8%, 9%). Abnormalities of heel walking were seen almost exclusively in del (del 11/60, dup 1/39). Frequencies of specific neurologic findings differed (p≤0.05) based on age group for speech articulation, appendicular tone, and spinal dimples in del and differed (p≤0.05) based on age group for neurocutaneous findings, spinal curvature, articulation, truncal and appendicular tone abnormalities, and hopping in dup.

Conclusions: Deletions and duplications of 16p11.2 are associated with a variety of neurological abnormalities, some of which may manifest differently depending on the age of assessment. While some of these neurologic abnormalities are common in populations with neurodevelopmental disorders, others – such as articulation and spinal abnormalities – may be more specific to 16p11.2 copy-number variations. Identification of these neurological abnormalities serves an important role in understanding the protean clinical consequences of these recurrent variants and their role in autism spectrum and other common neurodevelopmental disorders.