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"Confetti Skin, Beauty Within" is our blog about ichthyosis and its effect on our lives. Rachel and our three boys are affected with the form of ichthyosis called "icthyosis en confetti, type 2".

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Here's our summary of our best and most important posts of 2012.

Genetics Part 2 – Recessive Inheritance

Most rare types of ichthyosis are recessive. Recessive genes are genes that requires two copies, one from each parent, in order to make them show up. A person with only one copy of a recessive gene is called a carrier, and would have the same appearance as someone with two copies of the dominant version of the gene. The only way to know that you’re a carrier of something is if your parent has a recessive trait, or if your child is born with a recessive trait that seemingly comes out of nowhere.

Recessive does not mean “bad” or “disease,” and in fact some recessive genes are more common than the dominant version, and many recessive traits have no good or bad value at all. For example, having a hitchhiker’s thumb or having earlobes that attach to your head are caused by recessive genes. Having these things is neither bad nor a disease. Some genes, such as a not-brown eye gene in Europeans, (resulting in the majority having, grey, green, hazel or blue eyes) are more common than the dominant brown eye gene. Likewise, some dominant genes cause very aggressive or damaging disorders such as Huntington’s Chorea or Epidermolytic Ichthyosis, while the recessive genes are the normal ones!

Genes are expressed, or show themselves, at different rates in the population. 1 in 2 have type O blood, 1 in 4 have a hitchhiker’s thumb, and 1 in 100,000 have autosomal recessive congenital ichthyosis (ARCI).

Until recently, ARCI was known as lamellar ichthyosis and CIE or nbCIE and a few other names, but recently the names were changed because the old names were confusing. Regardless of the subtype, all recessive ichthyoses are inherited in the same general fashion. ARCI also includes harlequin ichthyosis and a few other very rare types like self-healing collodion baby.

A person has roughly 25,000 genes, and every gene has two copies. Every time we have a baby, that baby receives one copy from one parent, and the other copy from the other parent. For each child, the parents’ genes mix up fairly randomly prior to becoming sperm and egg, which is why some children look completely unrelated to their siblings, while others are mistaken for twins.

The most common question I have answered, ever, is “How did this happen to me? It has never been in my family before.

Imagine that we have a random gene, A. A is the dominant copy of the gene, and it will be expressed as long as at least one copy is in a child. Aa or AA both result in the dominant trait. Lowercase a is the recessive gene, and for it to appear, a person must have 2 copies, aa.

We set up a box, called a Punnett square, with the father on the top and the mother on the side. Let’s assume that we have a parent with normal skin and a parent with ARCI. Then we fill in the box with the letter from the matching top and side, and inside the box gives you all possible combinations in the children. As you can see, all children have Aa, which means that they will all be unaffected by ARCI because they have A, but are carriers of ARCI because they have a.

a Aa Aa
a Aa Aa

When you have unaffected parents, because ARCI is so rare, most of the time those parents are both AA. All of their children would be AA, also. But once in a while, an AA parent might have children with an Aa individual. As you can see from the box, half of those children would be Aa, half would be AA, but all of them would still be unaffected – as long as you have at least one A, you would still have normal skin.

a Aa Aa

Even more rarely, an Aa person will have children with another Aa person. Both have normal skin, but suddenly, a baby is born with ARCI, often after 2 or 3 normal skinned children. Take a look at this square and you can see what happened.

A a
a Aa aa

To the right is a picture showing what happened. There is a 25% chance of AA and 50% chance of Aa. Together, there is a 75% chance of having a normal skinned child. But there is also a 25% chance of having an affected child, aa. This doesn’t mean that once you have an affected child that no more will be affected. It’s like flipping two coins. Flipping 2 heads the first time you toss the coins has no impact on whether the next toss will be 2 heads, 2 tails or one of each. Some families will have 2-3 affected kids (like ours), while others will have no affected kids, and the majority will have 1 affected kid and the rest are unaffected.

Why don’t we test for ARCI? We know that somewhere around 1 in 130 people are carriers of some form of ARCI, as common (which is still pretty darn rare!) as 1/100 for CIE, 1/250 for lamellar and even fewer, maybe 1/500, carry the extremely rare harlequin ichthyosis mutation. For it to show up, both parents have to have the same mutation. One carrier parent of a harlequin mutation (ABCA12) having children with a carrier of lamellar (TGM1) will result in unaffected children.

Numerically, the chance that two carriers of ARCI will have kids is about 400 out of the 4 million babies born each year. However, because it is recessive, only 25% of those 400 kids, or 100, will actually be born affected.

Then, of those 100 kids, 95 will have CIE or lamellar, but only 5 will have harlequin.

The second most common question I have ever answered is, “If I have another baby, will this happen again? How do you know that it wasn’t just a spontaneous mutation and my other kids will be fine?” or, a variant, “Will I, an affected person, pass this on to my kids?

To answer this, we multiply.

  • If you are a carrier, you have Aa, and have a 50% chance of passing on either copy. So we multiply 1/1 (100% chance that you’re a carrier) times 1/2 (50% chance that you pass it on.). Then we multiply the other parent’s odds in the same way, and finally multiply them all together to get the total chance of passing things on.
  • If you are affected, you have aa so you’d multiply 1/1 (100% that you carry the gene) times 1/1 (100% chance that you pass it to the child).
  • If you don’t know if you’re a carrier, you multiply the chance that you’re a carrier times the chance that you’d pass it on (50%). So for a ARCI-lamellar type mutation, let’s say 1/250 are carriers and the carriers have a 50% chance of passing it on. So 1/250 times 1/2.

This makes a lot more sense in chart form:

Parents Parent 1 chance to have ARCI gene Odds Parent 1 passes mutant Parent 2 chance to have ARCI gene Odds Parent 2 passes mutant Multiply for total odds
2 random people plan children 1/100 or 1/250 or 1/500 1/2 1/100 or 1/250 or 1/500 1/2 1/100,000 1/250,000 1/1 million Here, you’re one of those 100 parents that get a surprise at birth
Surprise affected baby (both parents are carriers), planning more kids 1/1 1/2 1/1 1/2 1/4 Each child has a 25% chance of being affected with ARCI.
Affected person, random untested partner 1/1 1/1 1/100 or 1/250 or 1/500 1/2 1/200 or 1/500 or 1/1000 Odds are in your favor that your partner is any of 199, 499 or 999 unaffected people.
Affected person, partner is a known carrier of the same mutation 1/1 1/1 1/1 1/2 1/2 50% of children affected.
One parent is a carrier, the other had a spontaneous mutation of the same gene 1/1 1/2 1/200,000 1/2 1/800,000 Rare but possible, but on par with winning a lottery
Both parents spontaneously mutate the same gene at the same time 1/200,000 1/2 1/200,000 1/2 1/160 billion Impossible. There are only 7 billion people on the planet.

This is a series of posts on genetics. More information is available in the following links:
Genetics 1: What’s a Gene?
Genetics 2: Recessive Inheritance <–You Are Here
Genetics 3: X-Linked Inheritance (X-linked Ichthyosis)

Genetics 4: X-Linked Inheritance (CHILD Syndrome)
Genetics 5: Dominant Inheritance
Genetics 6: Mosaicism
Genetics 7: Video explanation of how mutations work
Genetics 8: Why we don’t do automatic prenatal screening for ichthyosis

3 comments to Genetics Part 2 – Recessive Inheritance

  • Heidi E

    Seriously? 1 in 130 are carriers of ARCI without knowing it?

  • Jennifer

    Roughly, but remember, you have to have the same sort of mutation for the problem to actually show up. Even with Lamellar or CIE, where there are several different genes involved, if one parent has a TGM1 mutation, the other parent still has a normal copy. Even if that other parent has an ALOX mutation, the first parent still has a normal copy, so the child would be unaffected even if he received both mutations from each parent. The only way to pass it on is if BOTH parents has a mutated copy of that TGM1 gene. It doesn’t have to be the same spot on the gene, it just has to be 2 broken copies of the same gene.

  • Hannah

    Very interesting, this will hopefully help to quell some of my partners concerns that he will pass on him lamellar ichthyosis to our future children! Thank you so much for explaining things in terms we can understand 🙂

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