16. Copy number variants at Chr16p11.2 and relevant clinical presentations

Recurrent microdeletions and microduplications on chromosome 16p11.2 (MIM: 611913 and 614671) confer susceptibility to autism spectrum disorder (ASD) in ∼1% of individuals with ASD, in addition to other clinical features. To further analyze copy number variants (CNVs) in this region, we studied 41 individuals with 16p11.2 duplications and 53 individuals with 16p11.2 deletions at Greenwood Genetic Center. They share common clinical features including: developmental delay, intellectual disability, autism spectrum disorder, seizures, and some features that are unique to either deletions or duplications. We summarize unique CNVs in individuals with either deletion (n=41) or duplication (n=35) of these regions. By overlapping the del/dup regions, we identify six subtypes of CNVs and classify them by potential relevant breakpoints based on size and location. Types 1, 2 and 3 are more common with both deletions and duplications found in these regions, and they overlap with BP1-BP3, BP1-BP2 and BP4-BP5 regions, respectively, in the literature. Types 4, 5 and 6 are less frequent, locating at 31.5-32.5 Mb, 29.6-47.5 Mb and 28.48-28.49 Mb regions on chromosome 16. Type 5 is found only in individuals with duplications and type 6 only in individuals with deletions. Type 4 variants are more frequently observed in individuals of African American decent, yet no clear association could be determined due to small sample size in this study. Genotype-phenotype correlation analysis was also performed to narrow down the potentially causative genes for specific clinical features. It is also worth noting that de novo CNVs are observed with much higher frequency in individuals with 16p11.2 deletions (68.2%, n=22) compared to those with duplications (28.6%, n=14). In conclusion, our analysis explores 16p11.2 CNVs in more detail for rarely observed regions, and could broaden the understanding of the clinical significance of genes and non-coding regions in this chromosomal region.