A basic Genetics 101 for SHANK2 video by Pilar Margoulas.
WHAT IS THE SHANK2 GENE?
The SHANK2 gene, located on the 11th chromosome in location 13 (11q13), provides the genetic code to produce SHANK2 protein. This protein is essential for proper brain function because it helps transmit messages from one brain cell (neuron) to another. When an error occurs in the gene, there is either too little or no SHANK2 protein available, which causes a loss of function.
Individuals with errors in their SHANK2 genes may be affected by:
WHAT IS THE ROLE OF SHANK2 IN BRAIN FUNCTION?
To understand the role SHANK2 protein plays in brain function, a brief explanation of neurology may help:
Neurons are the nerve cells in our bodies that send and receive sensory information to and from our brains, respectively. The human brain is estimated to have nearly 100 billion neurons. Each neuron is separated from its neighbor by a gap called a synapse. When one neuron sends a message to the next–using a chemical messenger called a neurotransmitter–the message crosses the synapse and is received on the next neuron by a receptor. A large number of receptors are found in a specific spot in the neuron — the postsynaptic density (PSD). In the PSD, SHANK2 works with other proteins, including SHANK1 and SHANK3, to build scaffolds. The scaffolds that are built support the receptors. Scientists theorize that diminished levels of SHANK2 protein make the scaffolds less effective. Consequently, receptors may not form properly or may not form at all leading to changes in brain function.
HOW ARE CASES DIAGNOSED?
SHANK2 variants are detected through whole genome sequencing (WGS) or whole exome sequencing (WES). Using blood or saliva samples, a person’s genome or a subset of the genome can be evaluated. Geneticists will review the patient’s WGS or WES report to determine if he or she has any pathogenic (disease-causing) genetic variants.
WHAT IS A SHANK2 VARIANT?
Despite how different we all are from one another, over 99% of the human genome sequence is the same for every person on earth. Differences in DNA sequences among the general population are called variants. Without variants, every human being would be identical. Some variants are harmless, and cause things like differences in eye color or height. These variants are considered to be neutral or benign. Other variants are harmful and are considered to be pathogenic or disease-causing because they lead to a functional change in the protein coded by that gene. Functional changes can lead to gain-of function variants which cause increased or changed protein production. On the other hand, loss-of-function variants lead to reduced or absent protein production. Individuals with SHANK2 are believed to carry these loss-of-function variants that result in differences such as autism or intellectual disability.
ALL OF THE FOLLOWING VARIANTS HAVE BEEN IMPLICATED IN SHANK2 DISORDERS:
HOW RARE IS A PATHOGENIC SHANK2 VARIANT?
Pathogenic SHANK2 variants are extraordinarily rare in the general population but are estimated to occur in between 0.15% and 0.3% of all individuals diagnosed with autism spectrum disorder.
IS THERE TREATMENT?
There is currently no treatment specific to SHANK2 disorders. However, treatments designed to address particular symptoms may improve the quality of life for an affected individual. Examples of treatments include applied behavioral analysis (ABA) therapy to improve behavior and augment learning, occupational therapy to enhance gross and fine motor skills, and medications prescribed to alleviate symptoms such as perseverative behavior (uncontrolled repetition) and ADHD.