University of Exeter Medical School, Exeter, UK
info@hyperinsulinismgenes.org
University of Exeter Medical School, Exeter, UK
info@hyperinsulinismgenes.orgWhat is inheritance?
Inheritance describes how an individual’s characteristics are passed from parents to their children through variants in their genes. Congenital hyperinsulinism is often caused by genetic variants that have been inherited from parents. Some variants cause disease when they are in one copy of a gene inherited from one parent, these are called dominant variants. Other variants only cause disease when present in both copies of a gene, these are called recessive variants. Someone who has a recessive variant in one copy of a gene is referred to as a carrier and will not have the condition.
Genes, chromosomes and genetic variation
We all have thousands of genes. Genes are small parts of DNA. DNA is the body’s instruction manual. Each person has two copies of each gene. One copy is from their mother, and the other copy is from their father. Genes provide a code to make proteins. Proteins help the body grow, function and stay healthy. It is normal to have some variation in this genetic code between individuals, this is what makes us all different. However, sometimes a change (or variant) in a gene can cause a protein not to function properly, leading to health problems. Disorders caused by genetic variants are often called genetic, congenital, or inherited conditions.
What happens in congenital hyperinsulinism?
In congenital hyperinsulinism, changes (called variants) in certain genes can affect how those genes work. This can cause proteins to be made incorrectly or not at all, which affects how the body controls insulin production and blood sugar levels. Variants in over 30 different genes can cause the hyperinsulinism, how these variants are inherited differs by gene and between individuals. That is why understanding the exact genetic cause of hyperinsulinism in your family is important for accurate diagnosis, treatment, and family planning. Details about the specific variant and how it has been inherited will be included in your genetic laboratory report.
How Congenital Hyperinsulinism Can Be Inherited?
There are three main ways that hyperinsulinism can be inherited. Although there are some rarer forms, such as X-linked inheritance, these are not covered here. The main inheritance patterns seen in people living with hyperinsulinism are dominant, recessive, and sporadic (which can lead to focal hyperinsulinism). Each of these inheritance types is explained in more detail in this leaflet.
In dominant inheritance, a person only needs to inherit one changed copy of a gene from one parent to have hyperinsulinism. Sometimes, the gene change happens for the first time in a child and is not inherited from either parent, this is called a de novo variant.
Changes in certain genes, such as ABCC8, GCK, GLUD1, HK1, SLC16A1, KMT2D, CACNA1D or HNF4A can cause hyperinsulinism when only one copy of the gene has a variant. If a parent has the changed gene, there is a 50% chance they can pass it on to their child and their child will develop hyperinsulinism.
In recessive inheritance, a child must inherit two changed copies of a gene, one from each parent, to develop hyperinsulinism. A child who inherits only one changed copy is called a carrier and is not predicted to have hyperinsulinism.
When both parents carry one changed copy of the same gene, each of their children has a 25% (1 in 4) chance of inheriting both changed copies and developing hyperinsulinism and a 50% (1 in 2) risk of inheriting one changed copy and being a carrier of hyperinsulinism. Recessive inheritance of hyperinsulinism has been seen with changes in the ABCC8, KCNJ11, HADH, and PMM2 genes.
Focal congenital hyperinsulinism involves changes in one of two genes: ABCC8 and KCNJ11. These genes code for proteins that make the potassium channel, also called the KATP channel. The KATP channel sits at the surface of cells in the pancreas and controls when insulin is released into the blood. In congenital hyperinsulinism, changes in these genes can cause the channel to stop working properly. As a result, cells in the pancreas release insulin even when blood sugar (glucose) levels are low, leading to repeated episodes of hypoglycaemia.
How does a focal lesion develop?
Focal disease happens when two separate genetic events come together.
Genetic event 1: First, a child inherits a single recessive variant in one copy of the ABCC8 or KCNJ11 gene from their unaffected father. This variant on its own does not cause congenital hyperinsulinism, which is why the father does not have the condition.
Genetic event 2: The second event occurs during the baby’s development in the womb. A cell in the pancreas loses the mother’s copy of the same gene and the father’s copy of the gene is duplicated. The cell then has two identical copies of the father’s gene, both of which have the variant. This is a random event that happens by chance within a cell in the pancreas.
This situation has two consequences within the pancreas: 1) the cell starts to multiply more than normal, producing lots of cells to form a focal lesion, 2) all these cells within the lesion have two copies of the variant causing them to release too much insulin.
What is the likelihood of having focal hyperinsulinism?
If an unaffected father carries a recessive variant in one copy of the ABCC8 or KCNJ11 gene, there is a 50% chance that he will pass it on to his child (genetic event 1). Most children who inherit the variant will be healthy carriers and will not have congenital hyperinsulinism.
A child develops focal congenital hyperinsulinism only if genetic event 2 also happens during pregnancy. This second event is estimated to happen in about 1 in 270 pregnancies. Overall, this means the chance of a father with a recessive ABCC8 or KCNJ11 variant having a child with focal hyperinsulinism is about 1 in 540 (less than 1%).
What is the likelihood that someone with focal disease will have a child with hyperinsulinism?
Most children of affected parents will not develop hyperinsulinism.
If the father has focal hyperinsulinism each child has a 50% (1 in 2) chance of inheriting the variant and being a healthy carrier (genetic event 1). For the child to develop focal hyperinsulinism genetic event 2 must occur. The likelihood of this is 1 in 540 (less than 1%). If the child’s mother carries a recessive variant in the same gene there is an increased chance of the child having diffuse congenital hyperinsulinism.
If the mother has focal hyperinsulinism each child has a 50% (1 in 2) chance of inheriting the variant and being a healthy carrier. If the child’s father carries a recessive variant in the same gene there is an increased chance of the child having diffuse congenital hyperinsulinism.
The likelihood that a parent with focal hyperinsulinism will have a child with diffuse hyperinsulinism is generally low. However, the likelihood increases in two specific situations: 1. The partner and the person with focal hyperinsulinism are related by blood or 2. Congenital hyperinsulinism is particularly common in the population that the two parents are from.
Variable penetrance means that not everyone who carries a genetic change will show the same symptoms of the condition. This is important to consider when thinking about the risk within a family. For example, in some dominant forms of hyperinsulinism caused by variants in the GCK, HK1, GLUD1, SLC16A1, or HNF4A genes, some people with the variant may have mild symptoms or none at all, yet can still pass the variant to their children, who may develop hyperinsulinism.
In recessive forms of hyperinsulinism, such as those caused by two variants in the ABCC8, KCNJ11, or HADH genes there can also be differences in how severe the condition is even between siblings who have the same two variants. The reasons why some people are more affected than others are not yet fully understood.
