User:Clearlykrystal/sandbox

These are the new sections still in development for the Kabuki syndrome page.

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 * Kabuki Syndrome Specific
 * GARD (Genetic and Rare Diseases Information Center) - NIH Center for Advancing Translational Sciences
 * GeneReviews - Clinically relevant and medically actionable information for inherited conditions
 * Genetics Home Reference - Kabuki Syndrome page
 * Genetics Home Reference - KDM6A gene
 * Genetics Home Reference - KMT2D gene
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 * Kabuki syndrome
 * Kabuki syndrome 1
 * Kabuki syndrome 2
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Causes [CS]
Kabuki syndrome is caused by a mutation in one of two genes, KMT2D (located on chromosome 12) or KDM6A (located on X chromosome). Before we discuss the specific genes that cause Kabuki Syndrome, let's review some of the general concepts in human genetics:

The genetic code provides the instructions for building proteins in the body. Proteins are often only thought of as the building blocks for muscles, but proteins in the body essentially perform all our basic functions; for example, they form the neurotransmitters in the brain, they form the enzymes that digest our food and they form the hemoglobin that transports oxygen from our lungs to tissues in the body.

The genetic code is made of an alphabet containing 4 letters: A for Adenosine, C for Cytosine, T for Tyrosine and G for Guanine. These nucleotide bases are the building blocks of DNA. The genetic code is translated from the language of DNA (the nucleotide bases ACTG) to the language of proteins (amino acids) via sequences consisting of 3 nucleotides called codons. For example, the codon GCA encodes the amino acid alanine. There are also codons that tell the cellular machinery to start and stop building a protein. The codon TAA is a stop codon.

Everyone has a set of 22 chromosomes that they inherited from their mom and a set of 22 chromosomes from their dad. You also have 2 sex chromosomes. If you are female you have two X chromosomes and if you are male you have an X chromosome from your mom and a Y chromosome from your dad. Even though we inherit half our chromosomes each from our mom and dad, these chromosomes are not exact copies. The genetic code is often altered from one generation to the next with the ultimate goals of biodiversity and natural selection. Changes in the genetic code can make organisms more fit for their environment, the changes can have no appreciable effect at all or changes can produce disease. The result of a particular gene sequence in an organism is called a phenotype. For example, eye color is a phenotype. The genetic code that results in blue eyes is different than the genetic code for brown eyes. Eye color is generally non-disease causing (non-pathogenic) and so the different genetic codes resulting in these different phenotypes are called polymorphisms. Mutations occur when differences in the genetic code cause disease. The genetic code can be altered in different ways; a base substituted for a different one or bases can be inserted or deleted. For example, the codon TAT encodes tyrosine, but if the first T were mutated into a A, the TAT would become AAT and now encode asparagine. This single base substitution resulting in an amino acid change is called a missense mutation. However, if the last T were mutated into an A, TAT would become TAA and result in a premature stop codon. When a single base substitution results in a premature stop codon, this is called a nonsense mutation. In contrast, single base insertions and deletions not only change the genetic code but also disrupt the reading frame. Suppose a wild-type genetic code is GCA-ATA-AAT-TCA. The corresponding wild-type protein would be Alanine (GCA), Isoleucine (ATA), Asparagine (AAT), Serine (TCA). Suppose the A that helps encode alanine is deleted; the sequence is now GCA-TAA-ATT-CA, which encodes Alanine (GCA) then a stop codon (TAA). The single base deletion has shifted the reading frame up by one base, resulting in a premature stop codon. This is referred to as a frameshift mutation.

As mentioned previously, all of us have two copies of each gene. Autosomal dominant inheritance occurs when only one defective copy of the gene results in disease. Mutations in the KDM6A gene are inherited in an autosomal dominant fashion. In contrast, mutations in KDM6A have an X-linked recessive inheritance pattern. A disease with recessive inheritance occurs when both copies of a gene are mutated. When only one copy is mutated, the individual does not show a disease phenotype and is called a carrier. Since females have two X chromosomes (one from mom and one from dad) and males have only one X chromosome, only females can be carriers of an X-linked recessive disease. Males (XY genotype) do not have the protection of an extra X chromosome, so if they inherit the mutated X chromosome from mom, they will have the disease. When female carriers have a male child, there is 50-50 chance that he will get the mutated X chromosome and display a disease phenotype. If a KDM6A mutation is identified in a male, the mother should undergo genetic testing to find out if she is a carrier. Sisters of the affected male should also be tested as they may be unaffected carriers. The sons of an affected male with Kabuki syndrome from a KDM6A mutation will get dad’s normal Y chromosome and be unaffected. However, all of the daughters will be carriers (assuming an unaffected, non-carrier mom).

Genetic mutations can be inherited from one generation to the next or they may be spontaneously generated (ie de novo). Because KMT2D mutations are autosomal dominant, unaffected carriers do not occur. Thus, the vast majority of KMT2D mutations occur de novo. That is, the parents are unaffected and the gene was mutated early in embryological development.

From gene to protein

Mutation v polymorphism

General types of mutations

Genes involves in Kabuki syndrome/inheritance/carrier

Genetic testing '''<-- Where does this fit best? Here, diagnosis, or screening?''' Clearlykrystal (talk) 13:25, 22 April 2018 (UTC)

Sample genetic report/nomenclature

Pathophysiology/Mechanism
Needs to be revised! Use to include epigenetics.

Is there a preference on the term for this section?

KMT2D, formerly known as the MLL2 gene, is located on chromosome 12 and is one of the genes involved in the development of this disorder.[7][8] A mutation in the KMT2D gene results in a loss of function for the protein this gene codes for, which is a lysine (K)-specific methyltransferase 2D enzyme.[4] KDM6A is another gene, that when mutated, can lead to kabuki syndrome.[9] This mutation produces a nonfunctional lysine (K)-specific demethylase 6A. This gene is located on the X chromosome.

These two genes belong to a family of genes called chromatin-modifying enzymes. Specifically these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. These enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. Epigenetic activation of certain developmental genes is impaired by loss of either enzyme and developmental abnormalities occur, leading to the characteristics of kabuki syndrome patients. The specific developmental genes have not been fully identified. It is seen that a majority of these cases are due to de novo mutations (those present in the subject but not in the parents).[8] It is important to note that a percentage of patients did not exhibit a mutation in either gene; other causes are currently being researched.

Screening [AD]
Although no screening tests have been ...

Management
Needs to be fleshed out.

Prognosis
Needs to be fleshed out.

Epidemiology
Needs to be fleshed out.

History
Not included in current page.

Research
Not included in current page. From AD: I am very excited/interested in creating a “research” tab. There are some really exciting things in the pipeline, including some possible therapies. I can explain in more detail in person but I think this will be an important contribution. I know of some key papers that would be important to include such as Benjamin JS, et al. Proc Natl Acad Sci U S A. 2017. https://www.ncbi.nlm.nih.gov/m/pubmed/27999180/