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Genetics of AHC. Tara Newcomb, MS, LCGC University of Utah June 29, 2012. Objectives. Overview of DNA, genes and chromosomes Inheritance – implications to AHC Genetic testing . DNA. DNA is a code that acts as the instruction manual for our body. Code – 4 letters: A, T, G, C. DNA. - PowerPoint PPT Presentation
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Tara Newcomb, MS, LCGCUniversity of Utah
June 29, 2012
Genetics of AHC
ObjectivesOverview of DNA, genes and chromosomesInheritance – implications to AHCGenetic testing
DNADNA is a code that
acts as the instruction manual for our body.
Code – 4 letters: A, T, G, C
DNADNA is organized into units called genes.
Different genes are expressed in different parts of the body and have different jobs.
DNAIn order for all of our DNA to fit into each
cell in our body, it is compressed and wrapped around proteins.
The end result are structures called chromosomes.
Chromosomes – help to organize our DNA and are key in how our DNA is passed on from one generation to the next.
ChromosomesTypically – we each have 46 chromosomes
in each cell.The chromosomes come in 23 pairs.We get 1 set of 23 from our father and 1
set of 23 from our mother
Changes in DNAChanges in DNA are called mutationsEveryone has mutations in his or her DNA Some mutations have no visible effectsSome mutations cause disease
Changes in DNADeletion/Duplication – extra or missing DNADeletion – come in different sizes
Different sizes:Whole chromosomeEntire genePart of a geneA few base pairs
Missing DNA – if the information is not there the body cannot read it to make a protein
Disrupt the pattern used to make the proteinMore is not always better – Extra DNA and extra
protein can also cause problems
Changes in DNAChange to the DNA sequence
Spelling error in the DNA sequenceCauses the wrong piece to be added to the
protein – the protein can’t functionOur body recognizes the error and breaks
down the protein
InheritanceInheritance patterns are how we describe
how genetic information is passed from one generation to the next.
In general –The egg or sperm from each parent has one
of each of the pairs of chromosomesThere is a 50% chance to pass on either
chromosome in the pairWhen the egg and sperm join together to
form the embryo – the embryo has a full set of 46 chromosomes – 23 from each parent.
InheritanceAutosomal DominantAutosomal RecessiveX-linked DominantX-linked RecessiveMitochondrialDe Novo Mutations (No Family History)
Autosomal RecessiveMutations needed in both copies of the
same gene to express disease.
A mutation in only 1 copy of the gene does not cause disease = carrier
25% chance for 2 parents who are carriers to have an affected child
Autosomal DominantA mutation is needed in only 1 copy of the
gene to cause disease – The copy with the mutation “dominates” over the normal copy.
An individual with an AD disease has a 50% chance to pass the disease on to each child
De Novo MutationIn many genetic diseases, the mutation in
the gene is not inherited from a parent, but is a new mutation in a child.
Mutations can occur in the creation of the egg or sperm or when the embryo is created.
Changes the recurrence risk
De Novo MutationIf a mutation is identified in a child and
neither parent has the mutation, the chance of the parents having another child with the disease is very low.
If the affected child goes on to have children of their own, the chance of them passing on the mutation is still 50%.
PenetrancePenetrance refers to whether or not all
individuals with a mutation in a specific gene – show symptoms of the disease related to that gene.
100% Penetrance = everyone with a mutation shows symptoms of disease
50% penetrance = half of all indivuals with a muation show symptoms of disease
Incomplete PenetranceIn some diseases, 2 people can have the
same mutation – 1 person will have the disease, the other person will not have the disease.
We do not always understand what causes one person to show symptoms of disease over another.
Variable ExpressivityChildren with the same disease – have
different symptoms of the disease.
Even 2 people with the same change in their DNA can have different symptoms.
Genetics of AHCUp to this point:
No single genetic cause has been identified for AHC.
Diagnosis of exclusionNo way for physicians to confirm a child has
AHC via a specific single test.
Genetics of AHCFamilial Hemiplegic Migraines
Some patients with AHC-like symptoms have had mutations identified in the following genes:CACNA1A, ATP1A2, SCN1A
Associated with FHM, family history of migraines is usually present
Mutations in these genes account for a very small number of individuals diagnosed with AHC.
Genetics of AHCMajority of cases are sporadic
No other family members with AHCFew familial cases
Multiple siblings with AHCMultiple generations with AHC
Different inheritance = Different genes?
How do we find a genetic cause for AHC?Then: Family Studies
Difficult with few families with more than 1 individual with AHC.
Usually need several generations to find an answer
Needle in a haystack
How do we find a genetic cause for AHC?Now: Whole Genome and Whole Exome
SequencingNew technology to look at all of the genes
in a person’s cells at once.Information overload?
WGSAdvantages
Provides all of the data from a person’s DNA at once.
Good tool for identifying a genetic cause when there is not a good single gene candidate
WGS – Disadvantages/HurdlesWe are all different
100’s of changes per individual compared to reference sequence.
InterpretationWhich one is the causative mutation ?
More specific studies usually need to be done.
Genetic CounselingImportant to help interpret ANY genetic
testing results.
Helps to put information into perspective for each family.
Taking the time needed with each family.
AcknowledgementsOur many physician collaborators and colleagues especially:
Kenneth SilverFrederic and Eva Andermann Alexis ArzimanoglouMohamad MikatiDavid GoldsteinErin HeinzenJoanna Jen
Alternating Hemiplegia of Childhood Foundation Especially: Sharon Ciccodicola , Lynn Egan, Vicky Platt, Jeff Wuchich
Association Française de l'Hémiplégie Alternante: Dominique Poncelin
Associazione Italiana per la Sindrome di Emiplegia Alternante: Rosaria Vavasorri
AHC Families and Children
Questions