Abstracts

Rationale: 16p11.2 copy number variants (CNVs) are a risk factor for autism spectrum disorders (ASDs) and related neurodevelopmental disabilities. The incidence and characteristics of epilepsy in people with these genetic variants has not been well described. Recently, mutations in the PRRT2 gene within this locus have been associated with benign infantile epilepsy (BIE). The aim of this study is to delineate the relationship between seizures and 16p11.2 CNVs through analysis of a phenotypically and genetically well-defined cohort.Methods: The Simons Variations in Individuals Project has developed a national cohort of probands and family members with 16p11.2 deletions (del) or duplications (dup). Phenotyping includes detailed medical and neurologic evaluation, and standardized neuropsychological testing and structural and functional neuroimaging. After initial evaluation determined subjects who had seizures or possible seizures, detailed telephone interviews were conducted. Analyses include only those whose seizure status is known based on medical records and interviews. Results: Sixty del and 33 dup probands out of 115 probands total (73 del and 42 dup) had adequate information to determine seizure history. Of these, 16 del (27%) had at least one seizure, and 13 del (22%) and 7 dup (21%) had epilepsy. Of the initial 37 thought to have seizures or possible seizures, 7 had paroxysmal non-epileptic events only. An additional 42 had been clinically referred for EEG but did not have seizures. Median age of seizure onset was 11 months (IQR 5-48 months). Four of the 20 subjects with epilepsy (2 del and 2 dup) had Benign Infantile Epilepsy (BIE), with epilepsy resolving by age 3, and 2 others (del) had a single seizure or cluster of seizures in infancy. Intractability was infrequent, occurring in 2 del (15%) and 2 dup (29%). In the deletions group, Full Scale IQ was lower in probands with seizures compared to probands without seizures (85 versus 78, p=0.03). Prevalence of ASD diagnosis was not different among probands with seizures and those without (7/25 del and 5/7 dup). Scores on the Social Responsiveness Scale were higher in those with seizures but only reached significance in the deletions group (SRS 68 vs. 92, p=0.006). Cortical malformations were not more frequently present in probands with seizures than in those without.Conclusions: Seizures occur in 1/5 of probands with 16p11.2 CNVs, with equal prevalence in deletions and duplications. The majority present in infancy or early childhood. Despite the frequently benign epilepsy course, trends toward lower IQ and greater social impairment were seen in those with at least one seizure or epilepsy. The high number of non-epileptic paroxysmal events emphasizes the importance of detailed ascertainment of seizures in studies of genetic variants and ASD. This is the first reported series of individuals with BIE due to CNVs at 16p11.2.