What is the probability that they would have another affected child what is the probability that they would have another child who is a carrier?

When a family has a child with congenital hyperinsulinism, a question often arises: Will any future child also have HI?

Inhaltsverzeichnis Show

Recessive Forms of HI
Dominant Forms of HI
Focal Disease Is Special
Decisions on Future Pregnancies
Delivering a Baby Known to Have HI

The answer, like many things concerning HI, is “It depends.” The type of HI in the first child and the parents’ genetics are important factors. And chance plays a big role.

Vicki Sanders, MS, LCGC, the genetic counselor in CHOP’s Congenital Hyperinsulinism Center, is available to review your family’s specific circumstances, but here are the basics.

Recessive Forms of HI

Most children with diffuse HI inherited it from a recessive gene. With this type of HI, both parents are carriers, and each parent passes on the gene for HI to the child. So, while the parents don’t have HI themselves, they carry the gene. For every pregnancy, there is a 1-in-4 chance the child will have HI, a 2-in-4 chance the child will be an unaffected carrier and a 1-in-4 chance the child will not be a carrier or have HI.

It should be stressed that each pregnancy has the same odds. Having one child with HI does not improve the chances that the next child will be a carrier or be unaffected. Imagine you were to flip a coin and it came up heads six times in a row. It’s unlikely, but it could happen.

There are multiple recessive forms of HI, with KATP-HI (caused by changes in the ABCC8 or KCNJ11 genes) being the most common type of recessive HI.

Dominant Forms of HI

If the child with HI has a dominant type, as a lesser number of children with diffuse HI do, they may have inherited it from one parent (who also has the dominant gene) or their HI mutation may have happened spontaneously, or “de novo.”

If it is a de novo mutation, there is only a tiny chance (about 1%) any additional children in the family will have HI.

However, if one parent has the same form of HI, even if they have mild or subtle symptoms and may not have previously recognized they were affected, each subsequent pregnancy has a 50% chance the child will inherit HI. It’s impossible to predict if the child’s HI will be on the mild or more severe end of the spectrum.

There are multiple dominant forms of HI, including some types of KATP-HI, hyperinsulinism/hyperammonemia (HI/HA), glucokinase, HNF1-alpha and HNF4-alpha, as some examples.

Focal Disease Is Special

The inheritance of the focal form of congenital hyperinsulinism is more complicated. Children with focal HI inherit one copy of the gene change from their father, who is unaffected, and a normal copy of the same gene from their mother. For focal HI to happen, the normal gene that was inherited from the mother is lost, and the gene with the change from the father makes a copy of itself. This means the child now has two copies of the genetic change with no normal copy of the gene. Only some cells in the pancreas have the two copies of the gene change. Therefore only some beta cells release too much insulin.

The chance that a subsequent pregnancy would inherit focal HI is less than half of 1%.

Decisions on Future Pregnancies

Families have a range of options if they chose to pursue a HI-free pregnancy or find out if a fetus has HI. “Families will make the very personal decision on how they choose to proceed,” Sanders says.

The most technologically advanced way is for the family to work with a fertility clinic and plan an in vitro fertilization (IVF) pregnancy. When the fertilized egg (embryo) is six or eight cells, one cell is removed for genetic testing. Only embryos testing negative would be implanted.

Some families choose prenatal genetic testing either with chorionic villus sampling (CVS), a biopsy of tissue from the placenta at 10 to 12 weeks, or amniocentesis, when a fine needle is used to withdraw a small amount of amniotic fluid at 15 to 20 weeks. Both procedures have a slight risk of miscarriage.

In addition to the options outlined above (pre-implantation genetic testing with IVF or prenatal testing), additional reproductive options include using a donor egg or sperm (depending on the parents’ genetics) in subsequent pregnancies or adoption. If a couple that is at higher risk to have a child with HI chooses not to do any testing before birth, they would need to make a plan with Endocrinology to monitor the child for HI right after birth until a diagnosis is confirmed or ruled out.

Sanders recommends that unaffected siblings wait until they are adults to have a genetic test, when they can make the decision themselves. If an unaffected sibling does test positive for being a carrier, their partner should also be tested to better understand if any of their children could have HI or be a carrier.

Delivering a Baby Known to Have HI

Knowing in advance a baby will have HI allows families to make a birth plan with the knowledge the newborn may have hypoglycemia (low blood sugar) at birth. The HI Center provides families an informative letter to give to their birth hospital that outlines steps for blood glucose testing and management of hypoglycemia.

The letter is also helpful for families that have declined prenatal genetic testing so the birth hospital has the protocols to keep babies safe if they do have low blood sugar. Directions for genetic testing, if that is needed, can also be provided. The HI Center is always available to consult with endocrinologists in hospitals all over the country — all over the world — if HI is suspected and/or confirmed.

Some families carrying a baby with diagnosed HI, especially those from across the United States, choose to give birth in the Garbose Family Special Delivery Unit (SDU) at CHOP, the nation’s first delivery unit in a pediatric hospital for babies with prenatally diagnosed birth abnormalities. There, the baby comes under the care of HI experts from the very beginning.

Sanders and the HI Center’s geneticist Jennifer M. Kalish, MD, PhD, will help you understand your family’s case and discuss options for the future.

Probability of Inheritance

The value of studying genetics is in understanding how we can predict the likelihood of inheriting particular traits. This can help plant and animal breeders in developing varieties that have more desirable qualities. It can also help people explain and predict patterns of inheritance in family lines.

One of the easiest ways to calculate the mathematical probability of inheriting a specific trait was invented by an early 20th century English geneticist named Reginald Punnett
. His technique employs what we now call a Punnett square. This is a simple graphical way of discovering all of the potential combinations of genotypes that can occur in children, given the genotypes of their parents. It also shows us the odds of each of the offspring genotypes occurring.

Setting up and using a Punnett square is quite simple once you understand how it works. You begin by drawing a grid of perpendicular lines:

Next, you put the genotype of one parent across the top and that of the other parent down the left side. For example, if parent pea plant genotypes were YY and GG respectively, the setup would be:

Note that only one letter goes in each box for the parents. It does not matter which parent is on the side or the top of the Punnett square.

Next, all you have to do is fill in the boxes by copying the row and column-head letters across or down into the empty squares. This gives us the predicted frequency of all of the potential genotypes among the offspring each time reproduction occurs.

In this example, 100% of the offspring will likely be heterozygous (YG). Since the Y (yellow) allele is dominant over the G (green) allele for pea plants, 100% of the YG offspring will have a yellow phenotype, as Mendel observed in his breeding experiments.

In another example (shown below), if the parent plants both have heterozygous (YG) genotypes, there will be 25% YY, 50% YG, and 25% GG offspring on average. These percentages are determined based on the fact that each of the 4 offspring boxes in a Punnett square is 25% (1 out of 4). As to phenotypes, 75% will be Y and only 25% will be G. These will be the odds every time a new offspring is conceived by parents with YG genotypes.

An offspring's genotype is the result of the combination of genes in the sex cells or gametes (sperm and ova) that came together in its conception. One sex cell came from each parent. Sex cells normally only have one copy of the gene for each trait (e.g., one copy of the Y or G form of the gene in the example above). Each of the two Punnett square boxes in which the parent genes for a trait are placed (across the top or on the left side) actually represents one of the two possible genotypes for a parent sex cell. Which of the two parental copies of a gene is inherited depends on which sex cell is inherited--it is a matter of chance. By placing each of the two copies in its own box has the effect of giving it a 50% chance of being inherited.

If you are not yet clear about how to make a Punnett Square and interpret its result, take the time to try to figure it out before going on.

Are Punnett Squares Just Academic Games?

Why is it important for you to know about Punnett squares? The answer is that they can be used as predictive tools when considering having children. Let us assume, for instance, that both you and your mate are carriers for a particularly unpleasant genetically inherited disease such as cystic fibrosis
. Of course, you are worried about whether your children will be healthy and normal. For this example, let us define "A" as being the dominant normal allele and "a" as the recessive abnormal one that is responsible for cystic fibrosis. As carriers, you and your mate are both heterozygous (Aa). This disease only afflicts those who are homozygous recessive (aa). The Punnett square below makes it clear that at each birth, there will be a 25% chance of you having a normal homozygous (AA) child, a 50% chance of a healthy heterozygous (Aa) carrier child like you and your mate, and a 25% chance of a homozygous recessive (aa) child who probably will eventually die from this condition.

If both parents are carriers of the recessive allele for a disorder, all of their children will face the following odds of inheriting it: 25% chance of having the recessive disorder 50% chance of being a healthy carrier 25% chance of being healthy and not have
the recessive allele at all

If a carrier (Aa) for such a recessive disease mates with someone who has it (aa), the likelihood of their children also inheriting the condition is far greater (as shown below). On average, half of the children will be heterozygous (Aa) and, therefore, carriers. The remaining half will inherit 2 recessive alleles (aa) and develop the disease.

If one parent is a carrier and the other has a recessive disorder, their children will have the following odds of inheriting it: 50% chance of being a healthy carrier
50% chance having the recessive disorder

It is likely that every one of us is a carrier for a large number of recessive alleles. Some of these alleles can cause life-threatening defects if they are inherited from both parents. In addition to cystic fibrosis, albinism, and beta-thalassemia are recessive disorders.

Some disorders are caused by dominant alleles for genes. Inheriting just one copy of such a dominant allele will cause the disorder. This is the case with Huntington disease, achondroplastic dwarfism, and polydactyly. People who are heterozygous (Aa) are not healthy carriers. They have the disorder just like homozygous dominant (AA) individuals.

If only one parent has a single copy of a dominant allele for a dominant disorder, their children will have a 50% chance of inheriting the disorder and 50% chance
of being entirely normal.

Punnett squares are standard tools used by genetic counselors. Theoretically, the likelihood of inheriting many traits, including useful ones, can be predicted using them. It is also possible to construct squares for more than one trait at a time. However, some traits are not inherited with the simple mathematical probability suggested here. We will explore some of these exceptions in the next section of the tutorial.