Tara Newcomb, MS, LCGC University of Utah June 29, 2012 Genetics of AHC

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