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