16p11.2

The 16p11.2 duplication is a copy number variant (CNV) associated with a wide variety of neurological and psychiatric features. The duplication occurs at approximately 3 in 10’000 births in the general population. Genetic and clinical studies have linked the duplication to varied diagnoses, including schizophrenia, autism, intellectual disability, epilepsy, and attention-deficit hyperactivity disorder. The duplicated region on chromosome 16 includes 29 genes (27 protein-coding) involved in neurodevelopment and synaptic function. Multiple model systems have been used to understand the impact of the duplication on brain function, including mouse models, stem cell and organoid models. Ongoing research is aimed at exploring the role of different genes within the duplication, and developing novel therapeutic targets for the condition.

Biological Function

The canonical 16p11.2 BP4–BP5 region spans approximately 600 kb and contains 27 protein-coding genes. Many of these genes are highly expressed in the brain, and regulate a diverse range of cellular functions including:

1) Neurodevelopment and synaptic function:

RRT2 and DOC2A are involved in synaptic function and vesicle trafficking.
MAPK3 (ERK1) and TAOK2 are part of the MAPK/ERK cascade essential for synaptic plasticity and cortical development.
KCTD13 is implicated brain development and synaptic function via RhoA signaling.

2) Transcription and chromatin remodelling:

HIRIP3, INO80E (chromatin), MAZ (transcription)

3) Metabolism:

ALDOA (glycolysis), CDIPT (phosphoinositide metabolism), and QPRT (NAD production), FAM57B (ceramide synthesis)

Phenotypes in 16p11.2 duplication mice:

Show reduced brain volume, hypoactivity, and deficits in cognitive flexibility.
Exhibit social interaction impairments, increased grooming and motor coordination issues, mirroring human neuropsychiatric features.
Display abnormal cortical layering
Altered cortical activity and synaptic function.

Mutations

The proximal 16p11.2 duplication involves a recurrent 600 kb region between breakpoints BP4 and BP5 on chromosome 16.
Most affected individuals inherit the duplication from one affected parent, but duplications can also arise de novo (16–29%). The inheritance pattern is autosomal dominant.
The 16p11.2 duplication is distinct from the reciprocal 16p11.2 deletion and the distal 16p11.2 duplication BP2-BP3.

Incidence

Estimated frequency is ~0.02% to 0.05% in the general population.
More common in individuals with neurodevelopmental disorders: ~0.4% in those with autism spectrum disorder (ASD) and 0.3% in those with schizophrenia (SZ).

Associated Conditions

Genetic studies have linked the duplication to multiple neurological and psychiatric conditions, including intellectual disability, ASD, schizophrenia and Rolandic epilepsy.
Clinically ascertained cohorts of duplication carriers have varied symptoms, including: intellectual disability, developmental delay, ASD, ADHD, microcephaly, and muscle weakness.

Research at Northwestern

Researchers in the P enzes lab have shown that two genes in the duplication are particularly important for the condition including:

PRRT2 – a gene involved in synaptic function. Genetic correction of PRRT2 rescues seizures, as well as social and circuit deficits in 16p11.2 duplication mice.
Read more. Also see press release.
MAPK3 (ERK1) – a gene involved in cellular signaling. Treating 16p11.2 duplication neurons with ERK inhibitors reverses excessive dendritic branching associated with the condition. Read more

Penzes lab has also shown that patient-derived induced neurons have deficits in network activity, dendritic outgrowth, and calcium regulation. Read more.

TThe impact of 16p11.2 duplication as well as other CNVs is discussed in this review.

Important publications from other laboratories

Weiss et al. (2008, Nature) — Landmark study describing 16p11.2 CNVs and their associations with autism and other neuropsychiatric conditions. Read more.
D’Angelo et al. (2016, JAMA Psychiatry) — First large-scale analysis of IQ, psychiatric, and medical diagnoses in 270 carriers of the 16p11.2 duplication. Read more.
Rein et al. (2020, Trends in Genetics) — Review of incidence, genetic and clinical studies, and disease mechanisms associated with 16p11.2 CNVs. Read more.
Auwerx et al. (2024, American Journal of Human Genetics) — Comprehensive review of the diverse symptomology in 16p11.2 duplication carriers, with emphasis on systemic (bodily) functions. Read more.

Genetic Testing

Testing via chromosomal microarray (CMA) can detect 16p11.2 duplications.
Also identified through exome sequencing and targeted CNV panels.
Genetic counseling is recommended due to variable expressivity and inheritance risks.

Clinical Trials

No active clinical trials
Patient recruitment for observational studies through Simons Searchlight are currently ongoing (link).

Patient advocacy organizations

Simons Foundation Autism Research Initiative (SFARI) – major funder of 16p11.2 CNV research and patient support.
Community support and resources are for individuals with rare CNVs are also available through RareChromo and NORD .

Social Media Resources

Facebook community

Further information

Gene Reviews https://www.ncbi.nlm.nih.gov/books/NBK11167/