Syndromes hidden within the 16p11.2 deletion region

Chromosome 16

16p11.2 is a region of chromosome 16 particularly prone to deletions and duplications.

Copy number variations (CNVs) are defined as specific regions within a chromosome that are either deleted or duplicated. CNVs can either be inherited or can occur spontaneously in patients during development. The effects of CNVs are difficult to define, as the severity of the symptoms varies from patient to patient – even in patients with CNVs in the same chromosomal region. Of particular interest is 16p11.2, a region within the short arm of chromosome 16 that is prone to both deletions and duplications. This article compares cases of 16p11.2 deletions and duplications to better describe the symptoms of these two CNV types. It also hopes to shed light on potential genes that are causing these symptoms, either when lost in deletions or replicated in duplications, and other factors explaining phenotypic diversity among carriers.

Potential genes that are responsible for producing the symptoms of a CNV can be discovered by comparing symptoms of patients with CNVs in similar chromosomal regions. In a recent study, 5 patients had overlapping 16p11.2 deletions, along with the symptoms of severe early-onset obesity and developmental delay. In all 5 cases, the SH2B1 gene was deleted within the 16p11.2 region. SH2B1 is involved in leptin and insulin signaling, which are key processes in metabolism and weight management.

Therefore, loss of this gene likely correlates to the symptoms of early-onset obesity. In contrast, 16p11.2 duplication carriers have lower body mass indexes on average, suggesting that overexpression of this region has the opposite effect as a deletion. Whether this is also caused by the SH2B1 gene has yet to be determined.

Both deletion and duplication carriers show intellectual disability and developmental delay as common symptoms. Speech delay and behavioral problems – including autism spectrum disorder and attention-deficit hyperactivity disorder – are common features of those with developmental delay.

However, while deletion carriers display language impairments, duplication carriers typically do not. This finding stresses the complexity of the CNVs, and how deletions and duplications can produce both similar (both cases cause intellectual disability) and contrasting (deletion cases have language impairments, duplication cases do not) neurodevelopmental symptoms.

This article successfully summarized the symptoms of the different CNV types within the 16p11.2 region. Deletion carriers typically display higher BMIs, intellectual disability, developmental delay, and speech delay. Duplication carriers typically display lower BMIs, intellectual disability, and developmental delay.

Loss of the SH2B1 gene is the likely source for the obesity symptoms in deletion carriers. While there are emerging answers for this symptom of 16p11.2 CNVs, more research needs to be done to discover potential genes pertaining to the intellectual disability and developmental delay symptoms.

The spectrum of lost genes is not the only factor causing the variability of clinical manifestations. The possibility of “unmasking” mutated genes on the homologous non-deleted segment of another chromosome 16 is another opportunity. Moreover, some components (promoters) of the MVP and MAPK3 genes located at 16p11.2 are involved in chromatin interaction with other genes (located outside of 16p11.2), and their malfunction leads to perturbed chromosomal organization as a whole.

Poot, et al. “Syndromes Hidden within the 16p11.2 Deletion Region”. Molecular Syndromology 2018, in press.

Important new research publications are reviewed by CDO geneticist and advisor, Dr. Iosif Lurie, M.D., PhD and important new summaries are posted monthly.  Assistance with synopses is provided by Colleen Donnelly.  For more information on the full text of any article please contact info@chromodisorder.org