Clinical and Molecular Spectrum of Proximal 16p11.2 BP4-5 Copy Number Variations: Insights From a Pediatric Cohort

Copy number variations (CNVs) at the proximal 16p11.2 BP4-BP5 locus are among the most well-characterized genomic regions associated with neurodevelopmental disorders. We aimed to define the clinical and molecular spectrum of these CNVs in a pediatric cohort. A total of 19 patients with pathogenic or likely pathogenic 16p11.2 BP4-BP5 CNVs were identified among 2200 individuals referred for chromosomal microarray analysis (prevalence: 1/116, 0.86%). Deletions were detected in 16/19 (84.2%) patients and duplications in 3/19 (15.8%). Developmental delay/intellectual disability was observed in 12/16 (75%) deletion carriers and 3/3 (100%) duplication carriers. Speech delay was present in 12/16 (75%) and 3/3 (100%), and motor delay in 6/16 (37.5%) and 2/3 (66.6%), respectively. Seizures were identified in 11/16 (68.7%) deletion carriers and 1/3 (33.3%) duplication carriers. Behavioral abnormalities were observed in 6/16 (37.5%) and 2/3 (66.6%), respectively. Neuroimaging data were available in 7/19 patients, with abnormalities detected in 5/7 (71.4%), all of whom had a history of seizures. Structural findings were heterogeneous and included ventricular asymmetry, corpus callosum thinning, and prominence of cerebrospinal fluid spaces. Additional systemic findings included endocrine abnormalities (6/19, 31.6%), skeletal anomalies (4/19, 21.1%), and ophthalmologic findings (3/19, 15.8%). These findings expand the phenotypic spectrum of proximal 16p11.2 BP4-BP5 CNVs and support their early consideration in patients with neurodevelopmental and neurological features, highlighting the need for multidisciplinary evaluation.