What is genetic testing, and how does it work?
Genetic testing can reveal variations in genes that may cause illness or disease. It can be done predictively, to assess a person’s risk of developing a condition, or diagnostically, to confirm a diagnosis. Before deciding to undergo pre-symptomatic genetic testing for Huntington’s disease, a person usually consults with a genetic counselor. The procedure is entirely optional, and the decision to undergo genetic testing can be emotionally difficult. Therefore, it’s important to understand how genetic testing works, its risks and benefits, and consequences of test results. Informed consent is necessary; more information on this process can be found here.
In general, genetic tests are performed on a sample of tissue or fluid. This can be a cheek swab, blood, urine, hair or amniotic fluid sample. Then, the sample is sent to a laboratory, where technicians analyze it and search for a change in protein level or in DNA.
For Huntington’s disease, the genetic test is performed on a blood sample. Once it is sent to the laboratory, technicians perform a DNA test to look at the huntingtin gene, and specifically, to check for the expanded CAG repeat characteristic of HD. The goal of the test is to measure the number of repeats in the huntingtin gene. More information on DNA mutations and the CAG repeat expansion in Huntington’s disease can be found here.
You can also watch a HOPES video on genetic testing here.
How does the genetic test for Huntington Disease work?
Laboratory technicians perform a set of steps to inspect the DNA provided in the blood sample. Let’s take a closer look at each of these steps.
Step 1- The Polymerase Chain Reaction: Making many DNA copies for analysis.
The polymerase chain reaction, or PCR, is used to isolate DNA and make many copies of it. It is needed in order to make lots of copies of the huntingtin gene, allowing scientists to examine it more closely. PCR produces millions of DNA copies in a short amount of time, and includes a few steps as follows.
First, the DNA sample is heated to nearly 100o C. DNA is normally double-stranded in a helix formation, but the heat causes the strands of DNA to separate into single strands. This process is called denaturation.
Then, the sample is cooled a little. Now, primers can bind to each DNA strand. These are small molecules serving as the starting material for a reaction called polymerization. The goal of this reaction is to create more DNA. An enzyme called DNA polymerase makes new DNA strands by adding nucleotides, the structural unit of DNA, to the primer on each strand. It’s like adding building blocks to a pre-existing block tower. As more nucleotides are added, the strand is extended, and eventually, a new copy of the gene is made.
Step 2- Gel Electrophoresis: Separating fragments of DNA based on size.
After creating millions of copies of the huntingtin gene using PCR, we are now ready to separate DNA fragments, in order to inspect them more closely. This can be done using a technique called gel electrophoresis. The principle is simple: DNA fragments are separated based on their size because smaller fragments are able to travel through the gel faster than larger ones. Let’s take a closer look at how exactly gel electrophoresis is done.
First, restriction enzymes attach themselves to DNA and cut it into small fragments. Then, the DNA pieces are placed in small wells in a gel floating horizontally in a buffer solution. This solution is located between two electrodes, one positive and the other negative. Once an electric current is passed through the gel, the fragments of DNA begin to move. DNA is negatively charged, so it is attracted to the positive electrode. The smaller fragments move faster than the larger ones, so they move across a greater distance towards the positive electrode.
Step 3- Inspection of DNA Fragments: How many CAG repeats?
Now that the fragments of DNA have been separated, the technicians are ready to inspect each DNA fragment. They do this to evaluate the number of CAG repeats in the huntingtin gene.
Individuals who do not have HD usually have 28 or fewer repeats. Individuals with HD usually have 40 or more repeats.
Information on test results and what they mean is available here.
For further reading
How is genetic testing done?
Huntington’s Disease and Genetic Testing.
Learning about Huntington’s Disease.
January 21st, 2016
This is a short story about Tommy and his family. Tommy is an 8th grader who loves learning about the brain. After his uncle is diagnosed with HD, Tommy decides to learn more about the neuroscience behind HD so that he can explain it to others.
Today is a Monday. It is Tommy’s first day back at school after Thanksgiving. He is sitting at his wooden desk slightly hunched over, cradling his head with his hands, fully alert. His eyes are fixed on his science teacher, Ms. Robinson, who is standing at the front of the classroom, flipping through her notes.
Tommy gazes at her expectantly. He has really been looking forward to today. Ms. Robinson had announced the day before Thanksgiving that when they return from the holiday, they would start a new chapter in biology—learning about the human brain.
Tommy has been waiting for this day since the very start of 8th grade. He has always found the brain to be fascinating, mysterious, and extremely powerful. Brains allow us to do anything we want. Thanks to your brain, you can sing, dance, laugh, cry, listen, write, study, run, jump, or play a sport. How is it possible that such complex thoughts and feelings come from a single place inside someone’s head?
For Christmas last year, when he was in the 7th grade, Tommy’s mother gave him a science textbook all about the brain. Tommy knew exactly what the gift would be when he picked it up, and he couldn’t help but smile widely. It was heavy, and he could feel the edge of the book’s cover. He unwrapped it and felt its untouched spine. Tommy was eager to run upstairs and start looking at it, but also wanted to preserve its pristine condition. On the front cover, he saw that it was a book for 11th graders. He felt a warm pride deep in his chest, grasped the book tightly and grinned at his mother.
Today, that book sits under Tommy’s bed at home. He brought it to school once, but it was pretty heavy to carry around. His friend Eric was curious to see the vivid illustrations in the book, and the two of them pored over it intently during recess. When Eric lost interest, Tommy tried to show his other friends, but they didn’t want to spend their playtime looking at a textbook. Tommy decided to bring it back home. He was a little upset, but his mother said that eventually his friends would be more receptive to hearing about how awesome brains are.
Tommy’s friend Eric always sits next to him in class, and this Monday morning is no different. He nudges a sleepy Eric under their shared desk, because the lesson is about to start. Tommy knows when Ms. Robinson is about to start teaching, because she always takes one last sip of coffee out of her dark red mug, and scribbles a little bit on the whiteboard to make sure her marker is working. He can tell that she is drinking coffee, because he can always smell its strong aroma from his seat at the front of the classroom. Tommy notices that she brought a clay model of the brain. He is resolved to pay attention to everything she says today, and to take notes furiously.
Ms. Robinson looks up at her class and launches into her lesson:
“Good afternoon, everyone! Today we will be discussing the human brain. As you all know, the brain is a complex organ that helps you think, move, and feel. In adult humans, it weighs about three pounds and looks like a large, greyish-pink walnut. Just like a walnut, it is divided into two hemispheres, split right down the middle. I brought a model today to help illustrate this. Do you see how the brain is split into two halves? The left half controls the right side of the body and human speech. The right half controls the left side of the body and how we perceive space. For example, it is responsible for the perception of how distant or close two objects are to each other.
Some scientists say that the specific functions of these two hemispheres are what make us uniquely human. They help us process at a higher level, which distinguishes us from other animals. This high-level part of the brain is the most recently evolved, and is known as the cerebral cortex. In fact, each hemisphere is divided into four lobes, which you can think of as four areas of the brain: the temporal, parietal, occipital, and frontal lobes. Most animals do not have a cortex, but we do. It helps us to be creative, feel emotions, and accomplish complex tasks.
Below this walnut-like structure, we find the more primitive part of the brain, located at the base of the head near the neck. This part of our brain is very similar to that of other mammals. It is responsible for our balance and for bodily functions that we don’t consciously think about, like breathing, regulating heart rate, and sleeping. All mammals need to accomplish these functions in order to survive!”
She pauses to take a sip of her coffee and clear her throat. Tommy takes a moment to catch up on the notes he is taking. Ms. Robinson asks the class: “Are there any questions so far?” A student in the back raises her hand. “I have two questions. Which side is the front of the brain, and which is the back? And how is the brain connected to the rest of the body?”
“Both great questions! The front of the brain is where the frontal lobes are. They are right behind your eyes. The base of the brain is closer to the back, and that is where the lower brain connects to the spinal cord. This is actually related to how the brain is connected to the rest of the body, which we will be discussing next!” Ms. Robinson beams at her class.
She continues: “The brain is part of the central nervous system. As such, it is made of nerve cells, which we also call neurons. These cells carry information, called an impulse, from your body to your brain, and from your brain to your body. So for example, if you touch something hot with your finger, a sensory receptor for heat on your finger will send an impulse to your spinal cord, which is in the central nervous system. Your spinal cord processes this information, and to avoid harming your skin, it sends an impulse back to your finger to say: “get away from the heat!” All this happens in less than a second, and you quickly remove your finger from the heat source. Your nerves connect the brain to different systems in your body, and also help muscles move in response to stimuli. So they actually help you do almost everything that you do in everyday life.”
Tommy pipes up: “Ms. Robinson, what is your favorite part of the brain?” She smiles at him, adjusts her horn-rimmed glasses, and says: “I really like the amygdala. It’s a very small structure above the primitive part of the brain, but below the cortex. It’s my favorite part of the brain because despite its small size, it is quite powerful. The amygdala is part of the limbic system, which is responsible for emotions, mood, and instinct. It also plays a role in attention and memory.”
At the end of the lesson, the bell rings- school is over for the day. Tommy grabs his backpack and follows Eric out of the room, shuffling his feet. His black and white Converse match Eric’s shoes. People often say that the two boys could be twins. They are the same height, and both sport a head of dark brown curls.
As they are walking through the yard towards the gate, Eric glances up at the line forming in front of the yellow school bus, and snorts. “How is it that the 3rd graders are always out of class before we are?” Tommy smiles, and looks for his younger sister Lily in the line. More specifically, he scans for a pink Dora the Explorer backpack, and quickly locates his sister. She is chatting excitedly with Eric’s little sister Madison. Tommy overhears her exclaim: “And we have leftover pumpkin pie!”
The boys join their sisters in line, and they clamor onto the bus. Eric and Tommy sit at the far back, and Madison and Lily sit right in front of them, as they have been doing all year. Eric unzips his backpack, rummages through it, and digs out a half-eaten sandwich. With his mouth full of cheddar cheese on rye, he asks Tommy: “So how was your holiday?
Tommy replies: “I had a lot of fun. My mom spent all day Wednesday and Thursday cooking. She made my favorite cheesy broccoli dish that we always have on Thanksgiving. The house smelled incredible! And my uncle, aunt, cousins and grandparents drove here all the way from Chicago.
“That’s awesome. Sounds pretty similar to my Thanksgiving!”
Eric trails off just as the bus slowed down in front of Tommy’s house. All four kids eagerly look out the window at the garden, because Tommy’s father, Joe, is usually watering the yard at this time of day. He is not there today, but typically waves at the children and aims the water hose at the bus as if he is trying to spray the kids when they hop off. Tommy wonders why his dad is not there today.
Both boys jump up out of their seats, and nudge their sisters to get up as well. The four kids hop out of the bus, and part ways. Eric and Madison live right across the street from Tommy and Lily, so they do not have far to go.
Tommy notices that his backpack is heavier than usual today, and sets it down in the driveway. He is still thinking about Thanksgiving. He really did enjoy the holiday, but he did notice that his Uncle Jacob, who is his father’s older brother, was not acting like himself. On Thanksgiving, Uncle Jacob bumped into the dining table a couple of times. He also mumbled a lot and seemed to hesitate before speaking. Tommy noticed that Uncle Jacob was not smiling as often. After the family meal, Tommy overheard his parents whispering in the kitchen that they were worried about him. They convinced Uncle Jacob to stay in town over the weekend to have a check-up with the doctor on Monday morning.
Tommy looks up at his sister. Lily runs up to the house just as their father, Joe, and Uncle Jacob pulled into the driveway. The two men sit in the car for longer than usual, but the kids do not take notice. Tommy grabs his backpack and follows his sister into the house. “Mom, we’re home!” Lily shouts. Their mom is on the phone, facing the floor-to-ceiling glass window in their living room. Lily runs to her, and hugs her from behind. Their mom hangs up the phone, turns around, and leans down to embrace her daughter. “Hi, sweetie. How was school today?”
Their mom made a light lunch for the kids. They gobble down some hot tomato soup with grilled cheese, and head upstairs to do some homework. Tommy had been excited to tell his mom about everything he had learned at school about the brain, but she seems distracted. As Tommy takes his empty plate to the sink, he notices that his mother is looking at the driveway with worried eyes. He gives her a hug. “Mom, is everything okay?” She looks down at her son and says: “I hope so, honey. I’m worried about Uncle Jacob’s health. Why don’t you head upstairs to do your homework and I’ll come upstairs later to chat?” Tommy nods and squeezes his mother extra tight.
He heads upstairs, sits at his desk and unzips his backpack to pull out his math notebook. Just as Tommy is putting pen to paper, his mother knocks at his bedroom door and asks to come in. Lily peeks in from behind her mother’s skirt. The rest of the house is eerily quiet. Tommy asks: “Where are Dad and Uncle Jacob?” His mother replies, “They went for a walk.” She enters her son’s room and sits on the bed. Lily plops down next to her and says innocently: “Mommy, what did you want to talk to us about?”
Their mom sighs. Tommy notices that her eyes are red and puffy. “Uncle Jacob is unwell. He has been diagnosed with Huntington’s Disease.”
Tommy’s stomach feels funny, and he stands up with shaky knees. He manages to walk over from his desk and sit next to his mother on the bed. She wraps her arms around her children and wipes away a tear. Lily looks both scared and sad. “Mommy, what does that mean?” Their mom continues: “We are still learning what this means. We know that it affects his brain, so Uncle Jacob will experience changes in how he thinks, moves, and feels. The doctors say that his condition will deteriorate over time, so it’s important to be grateful for the time we have together. It’s very important for us is to offer Uncle Jacob as much love and support as we can. When he and your father get home, give them both a big hug, okay?”
Soon after that, Joe and Uncle Jacob arrive back at the house. Tommy has never seen his father cry before, but he notices that his dad’s nose is redder than usual. Lily and Tommy had been sitting on the stairs, waiting patiently for them to get home. Tommy stands up, and walks over to Uncle Jacob. He extends a hand to his uncle, and helps him walk over the doorway. Uncle Jacob, whose hair is beginning to gray, smiles down at Tommy with crinkling eyes. “Thank you, Tommy.” Tommy buries his face in his uncle’s shirt, and Uncle Jacob holds him close. Lily, in the meantime, is hugging her father.
The following morning, the children sleepily munch on cereal for breakfast while their mother prepares their packed lunches to take to school. Knowing that orange juice is Tommy’s favorite part of the morning, Tommy’s mom decides to squeeze fresh orange juice for the kids to drink with breakfast. Uncle Jacob walks into the kitchen just as Tommy is gulping down the last of his juice. Lily smiles shyly at him. He stands at the doorway, and doesn’t make eye contact with anyone. Tommy’s mom glances at him with worried eyes. “Good morning, Jacob. Can I get you anything to drink? How are you feeling?” Uncle Jacob glances over at her, and manages a small smile. “I’m doing fine, thank you Sue for your hospitality. I think I’d like to hang out with the kids before they leave for school.”
Tommy is glad to see his favorite uncle join him at the table. He has never seen Uncle Jacob look sad before, and doesn’t really know how to act. Regardless, they chat about the upcoming day at Tommy and Lily’s school. Tommy quickly realizes that there’s no reason not to act just like himself! A few minutes later, Sue gently reminds the children that they need to make the bus, and everyone stands up to head outside to the curb. Uncle Jacob walks with the kids out the front door to see them off. Tommy hoists his backpack onto his shoulder and walks alongside his uncle. He notices that Uncle Jacob is not walking normally anymore. He is dragging his feet slightly, and also walking lopsided.
Eric and Madison are waiting on the sidewalk, watching the trio approach. Once Lily, Tommy and their uncle arrive at the curb, Madison looks pointedly at Uncle Jacob and asks: “You’re walking funny today.” Uncle Jacob cracks a smile but his eyes look sad. His voice trembles but he says: “I know. I have been feeling sick recently.” Tommy feels confused and sad. Madison shouldn’t have treated Uncle Jacob that way, even if she doesn’t know any better. She doesn’t even know Uncle Jacob that well.
Tommy hugs his uncle extra tight before boarding the school bus. He sits at the back next to Eric and leans his head against the glass window. People don’t understand why Uncle Jacob has been moving and behaving strangely. It probably has to do with changes to his brain, just like Tommy’s mother said. Tommy remembers his neuroscience lesson from yesterday, and decides he wants to learn more. He is resolved to find someone to explain it to him.
He would have asked Ms. Robinson if she knew anything about Huntington’s Disease, but his schedule does not include science class on Tuesdays. After school, Tommy runs upstairs to his bedroom and pulls the neuroscience textbook from last Christmas out from under his bed. Laying on his stomach on the bedroom floor, Tommy looks for a glossary at the back of the book. Under the letter “H”, he finds Huntington’s disease, and reads: “Huntington’s Disease is an inherited condition characterized by the breakdown of nerve cells over time. Progressive movement, cognition, and psychiatric symptoms tend to appear.”
The next day, there is no school due to a teachers’ in-service day. Tommy accompanies his father and Uncle Jacob to a doctor’s visit, and is feeling ready to ask some questions about Huntington’s Disease. Tommy sits in the waiting room during Uncle Jacob’s check-up, and peeks his head in at the very end to ask Dr. Peterson if he has time to answer a few questions. Dr. Peterson emphatically nods his head to say yes, and Tommy steps inside the room, walks over to the bed where Uncle Jacob is reclining but wide awake. Tommy leans against the side of the bed, resting his hand on his uncle’s shoulder. Joe is sitting in a chair near the doctor’s desk.
“Dr. Peterson, I really want to understand what happens in the brain when someone has Huntington’s Disease.”
“That’s great, Tommy. Why is that?”
“I find the brain really interesting, but more importantly, I want to be able to explain it to others who ask or are curious. People don’t seem to understand what Uncle Jacob is experiencing and I don’t want his feelings to be hurt.”
“Well, young man, I really appreciate your sensitivity, and I’m sure your uncle does too. I’d be happy to give you an overview of the disease. Huntington’s Disease is also known as HD. It is quite rare—it affects about one in every 10,000 people in the United States, and usually appears between 30 and 50 years of age. Many of the symptoms of HD can be explained by changes to the brain. There are movement, psychiatric and cognitive symptoms. Movement symptoms of HD can include muscle spasms, tics, rigidity, and difficulty speaking. There can also be uncontrollable movements like twisting and writhing. Symptoms affecting the brain include difficulty learning new things, and impairment of spatial perception. For example, Uncle Jacob mentioned to me that he bumped into the table during Thanksgiving, and that might have happened because he thought it was further than it actually was in real life.
There can also be difficulty planning and multitasking, since information processing in the brain is slowed and altered. Uncle Jacob sometimes has difficulty communicating with others, because is has gotten hard for him to organize words in his brain. Lastly, depression is a common psychiatric symptom for HD. So it’s important to show Uncle Jacob lots of love and support.”
“Thanks Dr. Peterson, that’s really helpful. So what is happening in Uncle Jacob’s brain?”
“Uncle Jacob’s ability to think, feel, and move is changing. This is happening because nerve cells, also known as neurons, in his brain are deteriorating in certain areas, like the basal ganglia and the cerebral cortex, which I’ll explain in a minute. HD is a progressive, neurodegenerative disorder: this means that over time, involuntary muscle movements develop, and the ability to think and remember deteriorates.
The disease affects the basal ganglia, which is part of a circuit linked to the thalamus. This part of the brain is most affected by the disease, and many of the symptoms result from damage to this circuit. The basal ganglia sits at the base of the brain, and is involved in the coordination of movement by muscles. In fact, the striatum in the basal ganglia is the first to lose nerve cells. As this happens, pathways between the basal ganglia and the motor cortex are damaged. This is why coordination of movement is affected in the disease. The motor cortex, usually responsible for the planning and execution of movements, can no longer do its job properly because it is not stimulated enough. This likely leads to the slow speed of motor movement of HD patients. Tommy, are you familiar with the word “cortex”?
“Yes, I am. We just learned about it in class yesterday. I know that the cortex is the high-level part of the brain in humans.”
“That’s right. If you were to look at a human brain, you would see gray on the outside and white on the inside. That’s because the cell bodies of our neurons are on the outside of our brains, and look gray: this part of the brain is the cortex. The extensions off those cell bodies project towards the center of the brain, and are white due to a fatty substance called myelin. Anyway, initial loss of cells in the basal ganglia leads to cell loss from other regions that are not getting feedback anymore. All of these things happen in the brain, and lead to behavioral symptoms that are visible to us.
“OK. You mentioned that there are emotional symptoms. Does something in the brain lead to that?”
“Indeed. Huntington’s Disease progressively damages the caudate nucleus, which is a relay station between the limbic system and the frontal lobes. The limbic system controls emotions, while the frontal lobes are really important in personality, in emotion regulation, and in responding to emotions. So in HD, there is a disconnect between emotion processing and response to emotions. This produces apathy or lack of interest, a common symptom of HD.
“Dr. Peterson, do we have a cure for HD yet?”
“Not yet, but researchers are hard at work trying to find one. There is a buildup of plaques in the brain that we still don’t understand, and lots of research is being done there. Scientists are currently trying to determine whether that is the cause of toxicity, because if so, we will know what to target for treatment. Meanwhile, there are therapies available to mitigate symptoms.”
“Thank you so much for explaining this to me.”
“Of course, I am happy to help. Let me know if you have more questions.”
Tommy shakes Dr. Peterson’s hand, and Joe stands up to leave. Along with Uncle Jacob, they make their way out of the office.
The next day is Thursday. It’s been exactly a week since Thanksgiving, but to Tommy, it feels like much longer. So much has happened, and his life feels like it has changed very much. At breakfast that morning, Tommy sits next to Uncle Jacob so that he can crack jokes and try to make his uncle laugh.
On the bus, Eric is playing with a Rubik’s cube. He and Tommy talk about the toy for a while, and marvel at how difficult it actually is to solve them. Madison and Lily, who are sitting in front of their brothers, notice how much fun the boys are having. They turn around to face Eric and Tommy, and watch the boys play with the cube. The four of them chat about the toy.
A while later, shortly before arriving at school, Tommy remarks to Madison: “Hey, do you remember the other day when my uncle was walking funny?”
She looks at him with large brown eyes. “Yeah. He said he was sick. I hope he’ll be ok!”
Tommy replies: “Thanks, Madison. He has Huntington’s Disease, which does not have a cure. Over time, his ability to think, feel and move will be affected more and more. I am hoping that we can all treat him with respect even if he moves or acts differently than we do. Over the week I spent some time learning about the changes that happen in the brain due to Huntington’s Disease, so if you’re curious about that I can try to explain it to you!”
Madison nods energetically. “I understand. Thanks for explaining that to me.”
Tommy smiles. “Of course!”
He sits back in the cushy bus seat, feeling much better. Tommy is confident that with the right words, he can help people understand that HD patients are just people too. Madison is a little young to hear about the changes HD causes in the brain, but he knows the knowledge will come in handy in the future. Tommy grips his backpack and excitedly sways his legs, eager to get off the bus. Maybe Ms. Robinson will have something to say about this too.
Up next: Tommy learns about the genetics of Huntington’s Disease. His cousin, Uncle Jacob’s son, is debating whether or not to get tested next year when he turns 18. Stay tuned for another short story, where Tommy learns about genetic testing and how HD is transmitted in families. More