When asking a patient if they have any genetic conditions or health concerns that run in the family, I’ve often had patients respond, “no, but does crazy run in families?!” On a more serious note, I’ve also had patients who are very concerned that autism, cancer, heart disease, or other conditions run in their family and what risk they may have to also develop the same condition or pass them on to their children. A genetic counselor is trained to take a family pedigree, or basically draw out a family tree, and ask specific medical questions about each family member. By drawing out a family pedigree and assessing each family member’s major medical history, a genetic counselor can often identify if there is a genetic condition or syndrome being passed down through the generations of a family. There are also specific patterns of how a genetic condition is passed down that a genetic counselor will look for in a family history to determine if your family does have a genetic condition.
First, let me explain what a pedigree looks like:
This first example shows how a typical family pedigree is drawn. Circles are females and always placed to the left in a marriage or partnership, and males are squares and typically placed to the right of the females. To connect a couple to their children, a line is drawn below vertically and then another line is drawn horizontally to show that the circles or squares below the couple are biological offspring of that couple. There are additional symbols for twins, miscarriages, infertility, etc., but this is the basics of a family pedigree.
Next, let’s talk about the common inheritance patterns of genetic conditions, or the different ways a genetic condition can be passed down in families. It’s important to learn about these inheritance patterns so that if someone is concerned about a health condition being passed down in their family, they can get an idea of whether to be concerned for themselves or their children.
This family pedigree has the same symbols as the example pedigree above. The main difference is there are circles or squares that are filled in black. This means that a person is affected by a disease or genetic condition.
The genetic condition portrayed by the filled in black circles and squares is an example of a genetic condition that is inherited in an autosomal dominant pattern. This means that the genetic condition is caused by one of two copies of a gene being altered, or one copy of the gene does not function correctly. By having one genetic variant in a gene associated with the genetic condition, the person will manifest the disease. Because only one copy of the gene needs to be nonfunctioning for a person to show symptoms of the genetic condition, each person in the family has a 50% risk to also inherit the nonfunctioning copy of the gene. For example, let’s say the pedigree above is showing a family history of a genetic condition called achondroplasia, or dwarfism. Achondroplasia is caused by a genetic variant in a gene called FGFR3. In line 1, person 2 is affected by achondroplasia due to a genetic variant in one of two copies of their FGFR3 gene. That person then passed on their genetic variant in FGFR3 to two of three children, line 2 person 3 and 5. For those two children, each of their children had a 50% risk of also inheriting the FGFR3 genetic variant. Three out of the four children for those two siblings also inherited the FGFR3 genetic variant.
The pattern to recognize for autosomal dominant is that you often can see the genetic condition in every generation of a family, and it affects both females and males.
The pedigree above is like the previous ones. The filled in squares and circles means that a person is affected by a disease. In an autosomal recessive genetic condition, both parents have to be carriers of the genetic condition in order for there to be a 25%, or 1 in 4 risk of a pregnancy being affected by the condition. If a person is a carrier of a recessive genetic condition, they are often healthy and do not have any symptoms of the condition, because only one of two copies of the gene associated is nonfunctioning. If a person partners with someone who also has one copy of the same gene that is nonfunctioning, they would also typically be healthy. The problem is if both partners pass their nonfunctioning copy of the same gene to a pregnancy, then the pregnancy would have both copies of the gene that do not function correctly, and that pregnancy would be affected by the condition.
It is common in family pedigrees to only see a recessive genetic condition show up in one generation. In the example above, no one is affected by the condition until the third generation, when two out of five children are affected. This is because it takes a couple matching as carriers for the same recessive genetic condition for there to be a risk of a child being affected by the condition. For example, a more common recessive genetic condition is cystic fibrosis, a disease of the lungs. Both parents must have a genetic variant in one copy of the CFTR gene in order for each pregnancy to have a 25% risk of inheriting both nonfunctioning CFTR genes from their parents.
The pattern to recognize in autosomal recessive genetic conditions is that typically they only show up in one generation of a pedigree and can affect both male and females.
This pedigree is an example of an X-linked recessive genetic condition. Some genetic conditions are passed down from mother to son, because they are carried on the X chromosome. Females have two X chromosomes and males have one X and one Y chromosome. A female can be a carrier and typically not affected by an X-linked recessive genetic condition because they have one copy of a gene on one X chromosome that is changed and nonfunctioning, but the other copy of a gene on the second X chromosome works fine. However, if a female passes her nonfunctioning gene on the X chromosome to a son, because males only have one X chromosome, he would be affected by that condition. If a female is a carrier of an X-linked recessive condition, each of her sons would have a 50% chance of being affected by that condition, and each of her daughters would have a 50% chance to be a carrier like herself.
In the pedigree above, it’s important to note that the only individuals filled in, or affected by the condition, are males. You can also see that most generations have at least one individual affected. This pedigree is often how an X-linked recessive genetic condition manifests itself in a family. One of the most well-known X-linked recessive genetic conditions is hemophilia, sometimes known as “the royal disease”. Hemophilia affected many royal families in England, Germany, Russia, and Spain due to Queens passing on their carrier status to affected sons and carrier daughters. Marriage was also common between royal families, which continued to pass on hemophilia to subsequent generations.
The key point to remember with X-linked recessive genetic conditions is they typically only affect males and can show up in multiple generations of a family.
A genetic condition inherited in an X-linked dominant pattern is similar to an X- linked recessive pattern in that the genetic variant occurs on the X chromosome. The difference is that all it takes is the one nonfunctioning copy of the gene on one X chromosome for the person to display symptoms of the genetic condition. This is why it’s called dominant instead of recessive. In this pattern, both males and females can be affected, although it’s still transmitted through the X chromosome. The pedigree above shows that a woman in line 1 is affected by an X-linked dominant condition. This means that her sons each have a 50% risk of inheriting the nonfunctioning copy of her gene and being affected by the genetic condition. Likewise, her daughters also have the same risk, a 50% risk of inheriting the nonfunctioning copy of the gene and being affected by the condition. In this pedigree, the female in line 1 passed on her nonfunctioning copy of the gene to a son and daughter. An unaffected daughter then partnered with an affected male of the same X-linked dominant condition (line 2 person 7) and since the male only has one X chromosome, each of his daughters automatically inherited the condition (person 8 and 10).
An example of an X-linked dominant genetic condition is Incontinentia Pigmenti, which is a condition that affects the skin, hair, teeth, and nervous system. It is caused by genetic variations in the IKBKG gene on the X chromosome.
It is important to note that some X-linked dominant conditions can be lethal in males, due to males only having one X chromosome. Key points to remember when looking at a family pedigree for X-linked dominant conditions are affected males will pass on the condition to all of their daughters, and males are only affected if their mother is also affected.
The inheritance patterns of genetic conditions that I’ve mentioned so far are the most common ways a genetic condition can be passed down in families. However, there is one additional way a genetic condition can be inherited and caused by a single gene variant, and that would be through mitochondrial DNA. Mitochondrial DNA is separate from the rest of our DNA, or genetic instructions. It is passed down maternally and can also become altered to cause genetic conditions. If a woman is affected by a genetic condition caused by a genetic variant in mitochondrial DNA, this means that each of her children will automatically be affected by the condition as well. Unlike our DNA outside of mitochondria, we only get mitochondrial DNA from our mother. If you look at the pedigree above, you’ll notice that all the children of an affected mother are also affected, but none of the children of an affected father inherit the condition.
An example of a genetic condition caused by a genetic variant in mitochondrial DNA is Leber hereditary optic neuropathy (LHON), which typically starts showing symptoms in a person’s teens or twenties and causes progressive vision loss.
Key points to remember for genetic conditions affected by mitochondrial DNA when looking at a pedigree: all children of an affected mother will also have the condition, and none of the children of an affected father will inherit the condition.
If you were looking at this pedigree and trying to find a pattern, it would be very difficult. You’ll notice that the condition looks like it skips a generation, as an unaffected male ends up with an affected son, and an affected mother has an affected daughter. Going through the different inheritance patterns, this pedigree doesn’t match very well with any of the patterns we have previously discussed. There are many health conditions that are caused by a combination of various genetic components and the environment. As a result, there often isn’t a pattern seen in families for conditions like this. However, by studying these conditions like diabetes, autoimmune diseases, and heart disease, we can see that families who do have individuals affected by these conditions tend to have an increased risk above the general population for other family members to be affected as well. The majority of multifactorial health conditions are much more common in the general population compared to single gene conditions.
What if I suspect that I have a genetic condition in my family?
If you are concerned that you have a genetic condition running in your family, please schedule an appointment with a genetic counselor. A genetic counselor can take a family pedigree and assess your risk of a genetic condition. In addition, a genetic counselor can discuss possible genetic testing options to identify the genetic variant running in your family. Please contact AT-GC to schedule an appointment with a genetic counselor.