Understand the genetics

It can be an overwhelming experience when a family member is diagnosed with a genetic disease such as SATB2-Associated Syndrome (SAS). Usually, a follow-up consultation with a geneticist is offered to address any questions that may arise. Nevertheless, we know from experience that many SAS families have additional and more advanced questions about the underlying genetics, even long after the initial diagnosis. Understanding how a variant in the SATB2 gene causes SAS may help determine which examinations are appropriate for a person and which future treatments may be suitable. We believe that informed parents and family members are better equipped to advocate for their loved ones.

Here is our introduction to the genetics behind SAS.

SAS - a genetic disorder with many names

SATB2-Associated Syndrome (SAS), also known as Glass syndrome and 2q33.1 microdeletion syndrome, is a genetic disorder.

Genetic disorders are medical conditions caused by mutations or variants (changes) in a person’s genes. These changes were introduced long before birth and can be inherited or spontaneous. Genetic mutations can alter how much of a certain protein is made, how it functions or how it interacts with other proteins. We all carry several mutations, but most of them are harmless. Only when a genetic mutation occurs in a vulnerable location can it lead to health problems and developmental challenges.

DNA, chromosomes and the SATB2 gene

From gene to SATB2 protein

Inheritance and SAS

Types of SATB2 mutations

There are different types of mutations or variants that can affect the SATB2 gene. Some variants are small, such as point mutations which only affect one "letter" (base/nucleotide) in the genetic code. Other variants are large and can span the whole arm of a chromosome. Understanding the type and span of a mutation helps predict its effects and can inform future research and treatments.

Nonsense mutations

Nonsense mutations happen when a point mutation introduces a stop codon in the wrong place of the gene. This leads to the corresponding protein being truncated too early. The truncated protein is usually degraded, but it may also persist and interact with other proteins. Since SATB2 proteins are believed to interact in clusters (so called dimers or tetramers), non-degraded mutated proteins may interfere with the function of healthy or normal SATB2 proteins. This is, however, still a research topic.

Frameshift mutations

Frameshift variants are caused by small genetic changes, usually a single letter missing or extra in the gene. An additional letter (insertion), for example, shifts the reading frame of the codons coming after the insertion, so that they translate into the wrong amino acids. Sooner or later, a stop codon is introduced, which truncates the mutated protein. The frameshift mutations are thought to have a somewhat similar effect to nonsense mutations, but since it is hard to predict any function of the added and faulty "tail" of amino acids, this may not be true in every case.

Missense mutations

Missense mutations happen when a single DNA base pair is changed, resulting in a different three-letter codon. The new codon instructs the cell to insert a different amino acid in that position in the protein. The effect of a missense mutation varies; it can have little to no impact, or it can alter the protein's function entirely. If the change occurs at a location where the protein interacts with other proteins, that interaction may be hindered or even prevented. The change from one amino acid to another may also alter how the resulting protein folds, potentially inhibiting most of its functionality.

The most common locations of SAS missense mutations are at p.389 and p.399 in the protein. SAS missense mutations at the same site but with different amino acid changes can result in different symptom severity.

Intragenic deletion

Intragenic deletions are small and fit inside a gene. A one- or two-letter deletion causes a frameshift mutation (as described above), but if the deletion doesn't change the reading frame of codons it is instead called an intragenic deletion. The resulting protein is missing a part, is shortened and may be misfolded in a way that makes it functionally different or entirely non-functional.

Larger deletions

Larger deletions can span parts of a whole chromosome or just the area of a few genes. Deletions that cover the beginning of, the end of, or the whole SATB2 gene give rise to SAS. Depending on what other genes are deleted, additional symptoms and disorders may arise. SAS individuals with larger deletions more often have growth issues and may need an echocardiogram to rule out heart abnormalities.

Duplications

Duplications happen when a genetic span is copied twice into the genetic code. Depending on the duplicated sequence, its location and size, the mutation can give rise to different and unique effects.

Translocations

Translocations happen when a piece of a chromosome breaks off and attaches to another chromosome. The translocation can be balanced – meaning the affected genes have switched place, or unbalanced – meaning genetic material is lost or increased. Symptoms depend heavily on which genes are involved and which genetic data are lost or added. Translocations involving the SATB2 gene may result in SAS.

Intronic mutations

Intronic mutations happen in parts of the gene called introns. Introns are not translated to amino acids, but instead regulate how the parts of the gene that do (the exons) are joined together. An intronic mutation can change which parts of the gene are translated and how these are spliced together.

Mutations in non-coding areas

Only 2% of our DNA codes for protein-producing genes. The function of the remaining 98% of DNA is still not well understood, but some of it is involved in gene regulation (enhancement or silencing). This means that mutations in non-coding DNA that regulates the activity or function of SATB2 can result in a SAS-like disorder. Only a few individuals with this kind of mutation have been identified to date.

Loss vs. Gain of function mutations

Genetic analysis

Different techniques can be used to find a genetic alteration in a person's DNA. Major chromosome changes can even be seen in a microscope, but to find smaller mutations, other options are available. Genetic panels can be used to check for mutations in sets of genes known to cause a specific symptom, such as an epilepsy panel, autism panel, or panels for intellectual dysfunction or craniofacial features. Some individuals will be diagnosed using a DNA microarray that analyzes chunks of genetic information missing or extra. But to detect smaller variants, WES - whole exome sequencing - is needed as it looks for all abnormalities in the protein-coding genes. An even more advanced option is the WGS - whole genome sequencing - that looks for variations across the entire genome. In the latter two cases, massive amounts of variants are found, and often a trio analysis is needed for the geneticist to rule out harmless mutations inherited from the mother or father.

The cost of genetic sequencing is much lower than before and genetic testing has become more available and more precise. This means that mutations that couldn't be detected 10 years ago might be detected today through genetic testing.

A genetic report is a summary of the findings from genetic testing. When a mutation is found to affect the SATB2 gene, this may result in the diagnosis of SATB2-Associated Syndrome (SAS). Typically nonsense mutations, frameshift mutations and deletions spanning the gene are straightforward and directly lead to a diagnosis. But if the person has a unique (often a missense) mutation in the SATB2 gene and lacks some of the typical features of the syndrome, or if the person has mutations in other genes that can cause similar symptoms, the SATB2 mutation may be denoted as a "Variant of uncertain significance" in the report. This means that there is not enough evidence to qualify the genetic change as the cause of SAS.

The report helps doctors:
• Identify a diagnosis
• Understand the likely cause of a person's symptoms
• Anticipate other potential challenges or strengths
• Offer guidance on preventative therapy, care options, and genetic counseling

Reading the genetic report

A genetic report often uses a medical vocabulary that can be hard to understand. While a clinical geneticist or genetic counselor can help you explain the report in more detail, it is good to have some basic understanding of the elements in it yourself. Below is a short guide to the vocabulary of your report and how to read the letters and digits of a specific mutation.

Variant: A change in the gene sequence - a "mutation" in layman's words.

Gene: The name of the affected gene, usually written in capital letters as in "SATB2". Note that an individual can have several mutated genes listed separately on the same genetic report. For larger deletions all the affected genes of that mutation are usually named together.

DNA change: Mutations are written in a code-like manner. The "c." corresponds to the mutation in the coding gene while the "p." corresponds to the mutation of the protein. The number is the location of the mutation within the gene or the protein. A single capital letter corresponds to one of four bases in the genetic code and the arrow between them shows which base was exhanged for which one. Three-letter codes like "His", "Lys" or "Arg" correspond to certain amino acids in the protein where the first one after the p. is the substituted amino acid and any a second one is the substituting one. Note that an * signifies that a stop codon was introduced.

Nonsense mutation: c.715C>T p.Arg239*

In the (c.) coding gene, at position 715, (C) cytosine was (>) substituted with (T) thymine.

In the resulting (p.) protein, the amino acid (Arg) arginine at position 239 was substituted so that a (*) stop codon was introduced.

Missense mutation: c.728G>A p.Arg243His

In the (c.) coding gene, at position 728, (G) guanine was (>) substituted with (A) adenine.

In the resulting (p.) protein, the amino acid (Arg) arginine at position 243 was substituted with the amino acid (His) histidine.

Frameshift mutation: c.799delA p.Thr267Leufs*3

In the (c.) coding gene, at position 799, a (del) deletion of (A) adenine occured.

In the resulting (p.) protein, the amino acid (Thr) threonine at position 267 was substituted with the amino acid (Leu) leucine. The (fs) frameshift mutation resulted in a (*) stop codon after (3) three amino acids.

Deletion: 2q33.1 microdeletion, (~1,32 Mb)

A genetic deletion occurred at the (2) second chromosome, (q) long arm, position 33.1, covering approximately 1.32 million base pairs.

Zygosity: Can be either heterozygous if only one gene copy (allele) is affected or homozygous if both gene copies are affected. In SAS, all known mutations are heterozygous.

Position: Where the mutation is located in the DNA. For example, "chr2" means it is located on the second chromosome and "exon 3" is a specific part of a gene.

Type of mutation: Nonsense / Missense / Frameshift / Deletion / Duplication / Translocation

See above for explanations of the different types of mutations.

Phenotype: Disorders that are related to the mutated gene. Smaller SATB2 mutations are often labeled with "Glass syndrome (OMIM #612313)".

Mode of Inheritance: Autosomal means that the mutation is not in one of the sex chomosomes and equally affects females and males. Dominant means that only one gene copy needs to be altered for the disorder to occur - as opposed to Recessive mutations.

Status: Can be Benign - a mutation with no health consequences, Pathogenic or Likely pathogenic - the mutation is considered to be associated with a disorder, or Variant of uncertain significance - it is not known if the change is associated with disease or not.

Key points to remember

More resources

The content provided by this website is for educational, communication and information purposes only and is not intended to replace or constitute medical advice or treatments. Always consult with your licensed healthcare provider.