Transcript Genetics of AHC

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
 DNA is organized into units called genes.
 Different genes are expressed in different parts of the body
and have different jobs.
DNA
 In 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.
Chromosomes
 Typically – 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 DNA
 Changes in DNA are called mutations
 Everyone has mutations in his or her DNA
 Some mutations have no visible effects
 Some mutations cause disease
Changes in DNA
 Deletion/Duplication – extra or missing DNA
 Deletion – come in different sizes
 Different sizes:
 Whole chromosome
 Entire gene
 Part of a gene
 A 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 protein
 More is not always better – Extra DNA and extra protein can also
cause problems
Changes in DNA
 Change to the DNA sequence
 Spelling error in the DNA sequence
 Causes the wrong piece to be added to the protein – the protein
can’t function
 Our body recognizes the error and breaks down the protein
Inheritance
 Inheritance 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 chromosomes
 There is a 50% chance to pass on either chromosome in the pair
 When the egg and sperm join together to form the embryo –
the embryo has a full set of 46 chromosomes – 23 from each
parent.
Inheritance
 Autosomal Dominant
 Autosomal Recessive
 X-linked Dominant
 X-linked Recessive
 Mitochondrial
 De Novo Mutations (No Family History)
Autosomal Recessive
 Mutations 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 Dominant
 A 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 Mutation
 In 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 Mutation
 If 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%.
Penetrance
 Penetrance 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 Penetrance
 In 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 Expressivity
 Children 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 AHC
 Up to this point:
 No single genetic cause has been identified for AHC.
 Diagnosis of exclusion
 No way for physicians to confirm a child has AHC via a specific
single test.
Genetics of AHC
 Familial 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 AHC
 Majority of cases are sporadic
 No other family members with AHC
 Few familial cases
 Multiple siblings with AHC
 Multiple 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 Sequencing
 New technology to look at all of the genes in a person’s cells
at once.
 Information overload?
WGS
Advantages
 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/Hurdles
 We are all different
 100’s of changes per individual compared to reference
sequence.
 Interpretation
 Which one is the causative mutation ?
 More specific studies usually need to be done.
Genetic Counseling
 Important to help interpret ANY genetic testing results.
 Helps to put information into perspective for each family.
 Taking the time needed with each family.
Acknowledgements
Our many physician collaborators and colleagues especially:
Kenneth Silver
Frederic and Eva Andermann
Alexis Arzimanoglou
Mohamad Mikati
David Goldstein
Erin Heinzen
Joanna 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