Genetics of AHC

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

2. Objectives • Overview of DNA, genes and chromosomes • Inheritance – implications to AHC • Genetic testing

3. DNA • DNA is a code that acts as the instruction manual for our body. • Code – 4 letters: • A, T, G, C

4. DNA • DNA is organized into units called genes. • Different genes are expressed in different parts of the body and have different jobs.

6. 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.

8. 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

11. 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

12. 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

13. 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

14. 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.

16. Inheritance • Autosomal Dominant • Autosomal Recessive • X-linked Dominant • X-linked Recessive • Mitochondrial • De Novo Mutations (No Family History)

18. 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

20. 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

21. 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

22. 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%.

23. 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

24. 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.

25. 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.

26. 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.

27. 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.

28. 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?

29. 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

30. 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?

32. 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

33. 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.

34. 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.

36. Acknowledgements Our many physician collaborators and colleagues especially: Kenneth Silver Frederic and Eva Andermann Alexis Arzimanoglou MohamadMikati David Goldstein Erin Heinzen Joanna Jen Alternating Hemiplegia of Childhood Foundation Especially: Sharon Ciccodicola , Lynn Egan, Vicky Platt, Jeff Wuchich Association Française de l'HémiplégieAlternante: Dominique Poncelin AssociazioneItaliana per la SindromediEmiplegiaAlternante: Rosaria Vavasorri AHC Families and Children

37. Questions