KAT6A 

KAT6A is very rare genetic mutation that was recently discovered and documented through genetic research.  

 

A KAT6A mutation is de novo meaning it is not inherited from the parents. People with a KAT6A mutation have similar traits and medical conditions. There are common features in all affected individuals; bi-temporal narrowing, broad nasal tip, low-set ears, thin upper lip, and or tented mouth, feeding problems, craniosynotosis, although other features such as ptosis (drooping eyelid), downturned corners of the mouth, micrognathia (small jaw), and smooth philtrum can only be seen in a subset of the people. Some children and adults have Global Developmental Delay or Intellectually Disability. Some children are developing typically and others are advanced. Many of the people have congenital heart defects. Some of the people have microcephaly.  Some have hydrocephalus, chiari, macrocephaly and other neurological conditions, but not all. To learn more please visit the traits and characteristics tab for in-depth descriptions.  There are 70 unique and beautiful people with KAT6A. The youngest diagnosed was 2 months old and the oldest diagnosed so far is 31 years old. We have kids reading, writing, talking, signing, playing piano, riding bikes, participating in an array of sports, and one person even has his driver's permit! They face many challenges but have no doubt they are very strong, smart and determined.

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Further Explanation of Genetics:

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Every individual has changes in his or her DNA. You have about 15,000 changes in your exome (the collection of all your genes--about 2% of your total DNA) that distinguishes you from people unrelated to you. Most DNA changes are not harmful. Some DNA changes, however, may cause medical conditions.

 

We look for DNA changes that:

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• Are rare in the general populations (<1%)

• Are predicted to be important (change protein sequence and function)

• are inherited from the parents or are new in the child make possible biological sense.

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     Genetic variants that satisfy the above criteria are then tested for potential involvement in your child's condition through testing in appropriate experimental models including:

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• Zebra fish embryonic models of development

• laboratory tests using your child's cells

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   The KAT6A gene (also known as MYST3) is located on chromosome 8. Each human has two copies of the KAT6A gene: one inherited from our mother and the other inherited from our father. Exome sequencing revealed a de novo heterozygous variant (a new DNA changed in only one copy of the gene that is not found in either parent) in the KAT6A gene in one child for example this variant is called 4273_5274delGT.  This means that 4,273 letters from the beginning of the gene KAT6A there is usually a G followed by a T, but in this case both of these letters are missing. 

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     The child's identified variant in the KAT6A gene causes a change in the reading frame of the DNA's instruction for coding KAT6A protein. What is a reading frame?  DNA letters are read three at a time with each triplet coding for an amino acid, or a protein block. When one or more letters are removed reading frame changes. Consider the sentence THE FAT CAT ATE THE RAT. If we remove the H and the E in the second THE, then try to read the sentence three letters at a time, we get: THE FAT CAT ATE TRA T. Thus, without the H and E in the second THE, the last two words no longer make sense. In this case the new reading frame caused by the deletion of two letters is predicted to code for a smaller protein that does not work properly. 

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     KAT6A codes for a protein that is important for regulating the activity of other genes. Recent reports have linked de novo heterozygous DNA changes (small letter insertions or DNA letter deletions) in KAT6A to a specific medical condition. The common clinical features observed in individuals with DNA changes in KAT6A are primary microcephaly and or Craniosynotosis (premature fusion of the bones in the skull), global developmental delay including profound speech delay, hypotonia (low muscle tone) cardiac defects and distinct facial features. Other clinical features can include vision problems, feeding difficulties 

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 All of the identified DNA changes in KAT6A are all De Novo, meaning they are not detected in the DNA of either parent. There is nothing that either parent could have done to cause a de novo change or prevent it from happening. 

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In general, the finding of a de novo variant can be due to two different possibilities:

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• Most likely, the change happened during conception or after conception and therefore was not inherited from either parent. In this instance, the chance of having another child with the same medical condition is very love, equivalent to the general population risk.

• It is also possible, however much less likely, that the variant was inherited from one of the parents but is only present in some of their cells. When a variant is only found in some, but not all, of a person's cells this is referred to as mosaicism. If a variant is only present in some cells of the body it may not be detected in DNA from blood. Individuals with mosaicism do not have the medical condition. If the variant is present in some of the reproductive cells (egg or sperm), then there is a small chance of having another child with the same medical condition. (3-4%)

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      Currently, it is not possible to evaluate if a person has germline mosaicism (the presence of the DNA variant only found in some, but not all, of the egg or sperm). However, there are several methods to test a developing fetus during pregnancy for DNA variants that cause genetic conditions. 

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     You're genome is all of your hereditary information or DNA. You have about 100 trillion (100,000,000,000,000)cells in your body and most of those cells contain 23 pairs of chromosomes. For each pair, one chromosome came from your father and one from your mother. Each chromosome is a tightly wound string of DNA made up of four types of molecules, commonly noted by the letters A,C,T and G. This four letter alphabet is the genetic code of DNA that contains information that determines in part the traits, such as eye color, height or disease risk, that are passed on from parent to child. You have about 3.2 billion (3,200,000,000) letters of DNA in the 46 chromosomes in each cell! This makes up your genome. 

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What is exome sequencing? 

Within your genome are about 30,000 genes. Genes are segments of DNA that serve as the instructions for your body. Only about 2% of your genome consists of genes.  The DNA that codes for the 30,000 genes is called the exome. Changes (or Variants) within genes can cause genetic conditions. Variants that cause rare conditions are more likely to be found in the DNA of genes as opposed to the DNA regions of the genome that do not have genes ( and whose functions are less well understood).  An efficient way to look for specific key variants in the genome is to look at the 32 million bases (letters of the DNA alphabet) inherited from each parent that comprise the exome (rather than scanning the entire 3.2 billion bases of the genome). You have about 15,000 variants on your exome that make you genetically unique!

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How was the exome analyzed?

     If a child's condition is genetic then it may be explained by one or more key variants in his exome. Since it is very difficult to determine which of a child's 15,000 variants may be important in explaining his condition, we also sequence the child's parents for comparison. This comparison allows us to see what variants he inherited from each parent and what variants are new changes in his exome.

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     By exome sequencing trips of family members (mother, father and child) we usually find about 100 variants that might contribute to the child's condition. We then compare those variants using online databases and software designed to predict the effect of the variants. We are usually left with about 10 key variants that could be involved in the child's condition. We then confirm that these are present in the child's exome using a second type of genetic test. If we are able to compare these variants to a healthy or affected sibling this may help us reduce the key variants even further. We then study those 10 variants in depth to determine whether one or more of them may be relevant to the child's condition. Some people have more than 10 candidate variants. The differences depend on each individual's unique genetic make-up. 

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What is a genome variant?

     A genome variant is a difference in the DNA (for example, a change from one letter to another). With the exception of identical twins, everyone's genome has thousands of differences from everyone else's. 

Some people spell "gray" with an "a," while others spell "grey" with an "e."

While the spelling is different the meaning is the same. However, some spelling differences are important and mean different things.  If it's raining, you want a "coat" with a "c," and not a "goat" with a "g." 

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     Many of a person's variants are harmless or benign ("a" versus "e" in gray/grey) while a few are key variants that make a difference to how a cell works ("c" versus "g" in coat/goat).

Some of these key variants may cause a cell not to work the way it's supposed to, but other key variants make us the unique people we are: freckled, fair, tall, etc.

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     When a sperm and egg combine to make a new genome, the chromosomes from each parent will match up to combine and make a unique set of chromosomes. The variants the sperm and egg genomes already carry will be transmitted to the new genome. Sometimes the sperm and egg already have similar key variants in the same gene or similar genes, the combinations of which may result in a disorder. Other times, the combining of the corresponding chromosomes can result in new changes not inherited from the parents and unique to the genome. (Called de novo variants).

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     An increasing number of people with medical challenges are undergoing exome sequencing, and as a result the scientific community is learning more about the genome every day. The gene was first identified as a potentially important cause during research in 2013 

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