16p11.2 Deletion Syndrome

16p11.2 copy number variations (CNVs) are increasingly recognized as one of the most frequent genomic disorders, and the 16p11.2 microdeletion exhibits broad phenotypic variability and a diverse clinical phenotype. We describe the neurodevelopmental course and discordant clinical phenotypes observed within and between individuals with identical 16p11.2 microdeletions. An analysis with the CytoScan Dx Assay was conducted on a GeneChip System 3000Dx, and the sample signals were then compared to a reference set using the Chromosome Analysis Suite software version 3.1. Ten patients from six separate families were identified with 16p11.2 microdeletions. Nine breakpoints (BPs) 4-5 and one BP2-5 of the 16p11.2 microdeletion were identified. All patients with 16p11.2 microdeletions exhibited developmental delay and/or intellectual disability. Sixty percent of patients presented with neonatal hypotonia, but muscle weakness improved with age. Benign infantile epilepsy manifested between the ages of 7-10 months (a median of 8 months) in six patients (60%). Vertebral dysplasia was observed in two patients (20%), and mild scoliosis was noted in three patients. Sixty percent of patients were overweight. We present six unrelated Korean families, among which identical 16p11.2 microdeletions resulted in diverse developmental trajectories and discordant phenotypes. The clinical variability and incomplete penetrance observed in individuals with 16p11.2 microdeletions remain unclear, posing challenges to accurate clinical interpretation and diagnosis.

This clinical review is designed to assist the pediatrician, family physician or internist in caring for the child, adolescent, adult and family in whom a diagnosis of 16p11.2 deletion syndrome has been confirmed by chromosome analysis. Although a pediatrician's initial contact with the child is usually within the first 5 years of life, occasionally an adolescent or adult will be tested and diagnosed after their sibling or child has been diagnosed with the same condition. Age specific guidance for the clinician is provided in Supplement Fig 1. 16p11.2 deletion is the most common genetic cause of neurodevelopmental disorders (1) and autism spectrum disorder (ASD) and is characterized by motor speech disorder, language disorder, motor coordination difficulties, some degree of developmental delay, below average cognition, learning disabilities in both verbal and nonverbal domains and psychiatric conditions. (Table 1) (2). While those with 16p11.2 deletion have some degree of development delay, the severity can vary significantly. Awareness and prompt attention to the issues is important in optimizing lifelong outcomes. There are no pathognomonic phenotypic features that can facilitate rapid clinical diagnosis, however, vertebral anomalies (often leading to scoliosis) (3), hearing impairment, cardiac malformations (3), congenital anomalies of the kidneys and urinary tract (4), slightly below average height (3), macrocephaly (3), and craniosynostosis (3) are noted in some individuals with the deletion. No patient will have all of these features.

Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.