Genetics Corner

Written for the AGSAA by Shannon Wieloch, MS, LCGC (www.storkgenetics.com)

Understanding genetics can feel overwhelming, especially when it’s tied to a rare condition like Aicardi Goutières Syndrome (AGS). In the Genetics Corner, we simplify complex scientific concepts to help families, caregivers, and patients better understand how AGS is inherited, and what this means for families. It’s a resource to empower you with knowledge and make sense of the genetic puzzle behind AGS.

Genetics Overview

DNA is the genetic information inside our cells that directs how our bodies grow and function.

Genes are segments of DNA that contain instructions for making proteins, which are essential for our bodies to work properly.

Genes are stored in structures called chromosomes.

Typically, humans have 46 chromosomes, made up of 23 pairs. We inherit one set of chromosomes from a human egg and one set from a human sperm. The first 22 pairs of chromosomes are called autosomes and are the same in males and females. The 23rd pair are the sex chromosomes. Typically, people assigned male at birth have an X and a Y sex chromosome, whereas people assigned female at birth have two X sex chromosomes.

Aside from genes on the X and Y chromosomes, humans typically have 2 copies of every gene. A genetic mutation, now commonly called a pathogenic or likely pathogenic variant, is a change in the genetic material that causes disease.

Current Genes Believed to be Associated with AGS

Currently, mutations in nine genes are known to cause AGS. These genes are TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, ADAR, RNU7-1, and LSM11. Mutations in these genes directly or indirectly turn a person’s immune system on when it is not needed, resulting in inflammatory damage to the brain, skin, and other body systems that lead to the characteristic features of AGS.

Genotype-Phenotype Correlations

The genetic makeup of a person is called their “genotype”. The observable symptoms of a person are called their “phenotype”. Genotype-phenotype correlations refer to a genotype being associated with a specific phenotype.

Though there is a wide overlap between the affected gene (genotype) and the clinical presentation (phenotype), some distinguishing features have been suggested. These correlations come from published papers on AGS, but it’s important to remember that what we are learning about AGS is always changing. What your affected person experiences may include what is mentioned below, but as more people are diagnosed, what constitutes AGS, our understanding of what AGS can look like, and what it means to have AGS will grow.

AGS Gene & Associated Phenotypes

RNASEH2B

Later onset
Hereditary spastic paraplegia (progressive weakness and stiffness in the leg muscles)

TREX1

Neonatal (newborn) onset

SAMHD1

Later onset
Cerebrovascular (conditions that affect blood flow and the blood vessels in the brain) disease
Mouth ulcers
Arthropathy (joint disease)
Glaucoma (vision loss due to damage of the optic nerve)
Hereditary spastic paraplegia (progressive weakness and stiffness in the leg muscles)

RNASEH2C

Early onset

ADAR

Later onset
Bilateral striatal necrosis (a condition where parts of the brain die, leading to issues with movement and coordination) and severe dystonia (muscle contractions)
Hereditary spastic paraplegia (progressive weakness and stiffness in the leg muscles)

RNASEH2A

Early onset

IFIH1

Later onset
Hereditary spastic paraplegia (progressive weakness and stiffness in the leg muscles)

Typically, the earlier the onset of symptoms the more severely a person is affected, however, a person’s phenotype may also be largely influenced by when they are diagnosed and more importantly when they start treatment. This is why newborn screening is so important for AGS.

How Aicardi-Goutières syndrome (AGS) is diagnosed

A clinical diagnosis is made by evaluating a person’s symptoms, family history, physical exam, and test results, including those from blood, lumbar puncture (or spinal tap), magnetic resonance imaging (MRI), and computed tomography (CT scan).

A genetic diagnosis is made through genetic testing. Genetic testing can identify changes in one of the genes that is currently known to be associated with AGS.

Because diagnostic journeys begin in the clinic, many people get a clinical diagnosis first and then use genetic testing to confirm or refine it.

A diagnosis of AGS is made based on physical symptoms, imaging of the brain, cerebrospinal fluid testing, and the results of genetic tests.

In an ideal world, a patient’s clinical diagnosis is confirmed with genetic testing. Unfortunately, this is not always the case, which can lead to confusion. We are still learning about AGS, not only what the clinical signs and symptoms are but what genes are associated with the condition and how specific genetic mutations impact the disease course.

AGS is extremely variable, both clinically and genetically. Sometimes only one genetic mutation is identified. Sometimes none are. Yet, your healthcare provider could still believe a person has a clinical diagnosis of AGS.

In those that are suspected to have AGS but who have not yet received either a clinical or genetic diagnosis, we see you and the additional struggle of being among the undiagnosed. But remember, our knowledge of what is clinically AGS and its genetic causes is changing daily and we hope you still find a connection and assistance through the AGSAA in caring for your affected person and yourself.

Pros and Cons of Genetic Testing

The answer to this is a personal one and will vary from one family to another.

For some, understanding the underlying cause, the why or what of a condition, is comforting. Others may hope to better understand the potential prognosis or outcome of a condition to plan for the future and manage expectations. This reason may be particularly meaningful for people pursuing a diagnosis of AGS as older literature highlighted severe cases while newer research is shedding light on variable forms of the condition. Another possible value is a diagnosis’ potential impact on future screening recommendations, treatments options, and access to financial assistance and services. Finally, it may help those who are considering (additional) children make more informed or different reproductive choices.

On the other hand, receiving information about genetic risk can cause anxiety, stress, and depression. In addition, some families are not interested in genetic testing for fear of having a label put on them. Other factors to consider include the risk of genetic discrimination, inconclusive results or variants of uncertain significance (see below), and financial cost.

Genetic Testing in Individuals Affected by AGS

Genetic testing is available for patients who have a clinical or suspected diagnosis of AGS. Testing may include a multi-gene panel, whole exome sequencing, or whole genome sequencing.

A multigene panel includes genes known to cause AGS and possibly other genes of interest known to cause a similar phenotype to AGS. Whole exome sequencing (WES) and whole genome sequencing (WGS) are more comprehensive testing options. WES looks at the coding part of the genes (i.e., the parts that contain directions to make proteins). WGS looks at all of the DNA, including both coding and noncoding regions of the DNA (i.e., the parts that do not code for proteins but can still affect a gene’s function). WES and WGS are typically considered when previous testing has not led to a genetic diagnosis.

Of note, research has suggested that WES is not good enough to detect mutations in the RNU7-1 gene. Therefore, it’s recommended that in patients suspected to have AGS, a special testing method called Sanger Sequencing be performed. Sanger Sequencing is a method used to look at the makeup of a small targeted area of DNA.

Types of Test Results

Genetic tests can have three possible results.

POSITIVE indicates that a mutation that is known to be disease causing was identified in the genetic material tested.

NEGATIVE indicates that no mutations that are known to be disease causing were identified in the genetic material tested. However, a negative genetic test may not absolutely rule out a genetic diagnosis of AGS. For example, there may be a type of mutation that causes AGS that the test was unable to detect or a gene associated with AGS that has yet to be discovered.

VARIANT OF UNCERTAIN SIGNIFICANCE indicates that a potentially detrimental change was identified in the genetic material tested, however, it is not known if the change is disease causing or benign because it has not been reported as such to genomic databases.

Inheritance

AGS can have different inheritance patterns. In most cases, AGS is inherited in an autosomal recessive manner. In other cases, it can be inherited in an autosomal dominant manner. In some patients affected with AGS, the mutation was not inherited but occurred spontaneously in that person. This is called a de novo mutation. The inheritance of AGS in a given family can provide information on the chance for other family members to be affected.

Autosomal Recessive Inheritance

Typically, AGS that is caused by mutations in the ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, LSM11, RNU7-1, and SAMHD1 genes are inherited in an autosomal recessive manner. Autosomal means that males and females can be affected by the condition in equal portions. Recessive means that both copies of the gene need to have a mutation in order for the person to have AGS. Typically, parents of children with autosomal recessive AGS have one copy of a typical gene and one copy of the mutated gene, and are known as carriers. Carriers usually do not have symptoms of AGS.

When both parents are carriers of AGS, there is a 25% chance in each pregnancy that a child will inherit both mutated genes. Though there have been cases in which a person with two mutations is not affected, the current thought is that having mutations in both AGS-associated genes will result in a child being affected.

Of note, each pregnancy is an independent event; the outcome of the last pregnancy does not impact the odds of which gene will be passed on in the next pregnancy. Below shows the possible outcomes of each pregnancy.

Autosomal Dominant Inheritance

Mutations in the IFIH1 gene and certain severe mutations in the TREX1 or ADAR genes are inherited in an autosomal dominant pattern. Dominant means only one copy of a gene needs to have a mutation in order for the person to have AGS.

In rare cases, asymptomatic individuals carry an AGS-associated mutation. When an asymptomatic parent has an autosomal dominant mutation in an AGS-associated gene, there is a 50% chance of passing the mutated gene on in each pregnancy, however the chance a child will develop AGS is unknown as research currently indicates it may take more than a mutated gene alone to trigger the auto inflammatory response in a person’s body that causes the signs and symptoms of AGS.

De novo

Sometimes mutations that cause AGS are not inherited but rather are caused by a new mutation in the affected person. These are known as de novo mutations and occur randomly due to errors in DNA replication during prenatal development.

If a child is identified to have a de novo mutation, the chance for the parents of that child to have another affected child is presumed to be slightly higher than the general population (though still <1%) because of the theoretical possibility of parental germline mosaicism.

Germline mosaicism means that some portion of the sperm or egg cells a person has have an AGS-associated mutation while other sperm or egg cells do not.

Reproductive Testing Options

Family Variant Testing

When someone in a family has AGS, other family members may have an increased chance of being affected or of having an affected child. Therefore, it is recommended that anyone known to carry a mutation in an AGS-associated gene share their specific test results, including the affected gene and specific mutation, with their relatives. This enables family members to pursue genetic testing for themselves. This is often called family variant testing (FVT). FVT can be done at any time, but if someone would use the information for reproductive decisions, it is best to do it before pregnancy to allow a person or couple to have a larger number of options.

Carrier Screening

Carrier screening is sometimes offered to a patient prior to or during pregnancy as a way to assess if they have an increased chance of having a child with certain genetic conditions. It is important to know that a negative carrier screen result does not guarantee that a child will not be affected with AGS. This is because the carrier screen may not include a specific family mutation, may not test for the type of genetic mutation that can cause AGS, may not look at the entire gene associated with AGS, or may not include every gene known to cause AGS.

Prior to Conception

Preimplantation genetic testing for single-gene conditions (PGT-M) is a way to help reduce the chance of passing on inherited conditions like AGS. It is done after an embryo is created via in vitro fertilization (IVF) to look for familial AGS mutations.

Talking to a reproductive genetic counselor before starting IVF is highly recommended as they can explain each step, review the benefits and limitations, discuss the timeline, and help coordinate the process.

During Pregnancy

Chorionic villi sampling (CVS) and amniocentesis are the only two tests during pregnancy that can detect known family mutations associated with AGS.

Done between 11-13 weeks of pregnancy, CVS involves obtaining a small sample of the placenta, specifically the chorionic villi, and testing the genetic material within those cells. The procedure is done either by inserting a small catheter into the vagina or inserting a thin needle through the abdomen. Both are done under ultrasound guidance. The chance of miscarriage after the procedure is estimated to be between 1 per 100 to 1 per 200, or 0.5% and 1.0%.

Done after 16 weeks of pregnancy, an amniocentesis involves obtaining a small sample of amniotic fluid and testing the genetic material within the amniotic cells. This procedure is done by inserting a thin needle through the abdomen under ultrasound guidance. The chance of miscarriage after the procedure is estimated to be between 1-3 per 1000, or 0.1% and 0.3%.

Talking to a reproductive genetic counselor prior to either procedure is highly recommended as they can review the additional benefits and limitations of these testing options.

Alternative Reproductive Options

Adoption

If you and/or your reproductive partner carry AGS-associated mutation(s), you could choose to adopt. Though there is no guarantee that your adopted child will not have AGS. The chance would be similar to the chance in the general population.

Donor egg, sperm, or embryo

Using a sperm or egg donor who has had negative carrier screening, specifically for the AGS-associated gene you know you or your partner have a mutation in, would reduce the chance of having a child with AGS, though the chance would not be zero. If the donor has not had carrier screening, many donor banks are willing to work with clients to have the donor tested, if asked.

The chance for a donated embryo to have AGS would be similar to the chance in the general population.