Genetics & CMT Q&A Questions from the CMTA Genetics & CMT Discussion Forum

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Dora Holland
5 years ago
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1 Genetics & CMT Q&A Questions from the CMTA Genetics & CMT Discussion Forum Presented by : Shawna Feely, MS, CGC & Carly Siskind MS, LCGC

2 Is CMT a type of Muscular Dystrophy (MD)?

3 Myopathy: a disease of the muscle MUSCLE Neuropathy: a disease of the peripheral nerve NERVE Is CMT a type of Muscular Dystrophy (MD)?

4 CMT: Hereditary Peripheral Neuropathy Genetic Condition Affects the long nerves that go to hands/feet Many forms can be divided into types The way it is passed along in a family How it is affecting the nerve Can you have a diagnosis of CMT without genetic testing?

5 CMT Autosomal Dominant X-Linked Autosomal Recessive Demyelinating (Type 1) Axonal (Type 2) Intermediate or Axonal (Type X) Demyelinating or Axonal (Type 4)

6 CMT: Hereditary Peripheral Neuropathy Genetic Condition Affects the long nerves that go to hands/feet Many forms can be divided into types The way it is passed along in a family How it is affecting the nerve Defining the exact type of CMT does require genetic testing Not everyone decides to do genetic testing Genetic testing can not determine the cause for everyone Can you have a diagnosis of CMT without genetic testing?

7 Genetic Testing Pros To determine if other family members are at risk Family planning Possible access to treatment trials to further research Having a definitive diagnosis

8 Genetic Testing Cons May have inconclusive results what then? Emotional impact of positive or negative results May not have a genetic test available Genetic Discrimination

9 Yes, let s start with a few definitions: De novo mutation a change in the DNA that occurs in a person but is not present in either parent Mutation any change in the DNA of a gene that causes an abnormal protein to be made Dominant inheritance a person needs to have a change in the DNA in only one of the two genes in order to be affected with the condition Recessive inheritance a person needs to have a change in both copies of a gene in order to be affected, having only one change means that a person is a carrier and does not have CMT Is it possible to have CMT with no family history?

10 How do I get genetic testing done in an affordable way?

11 Genetic Causes of CMT CMT subtype Gene CMT subtype Gene HNPP PMP22 (deletion) CMT4A GDAP1 CMT1A PMP22 (duplication) CMT4B1 MTMR2 CMT1B MPZ CMT4B2 SBF2 CMT1C LITAF/SIMPLE CMT4B3 SBF1 Genetic Testing can be complicated! CMT1D EGR2 CMT4C SH3TC2 CMT1E PMP22 (point mutation) CMT4D NDRG1 CMT1X GJB1 (Cx32) CMT4E EGR2 CMT2A MFN2 CMT4F PRX Many, Many Genes Associated with CMT (73 to date) CMT2B RAB7 CMT4G HK1 CMT2B1 LMNA CMT4H FGD4 CMT2B2 MED25 CMT4J FIG4 How do we know: What to test? Where to test? Cost of testing? CMT2C TRPV4 CMTX4 AIFM1 CMT2L HSPB8 CMTX5 PRPS1 CMT2D GARS CMTX6 PDK3 CMT2E NFL HSAN 1A SPTLC1 CMT2F HSP27/HSPB1 HSAN 1C CPTLC2 CMT2K GDAP1 HSAN 1D ATL1 CMT2L HSPB8 CMT DI C YARS CMT2M DNM2 CMT DI E INF CMT2N AARS CMT DI F GNB4 CMT2O DYNC1H1 dhmn 2C HSPB3 CMT2P LRSAM1 dhmn V BSCL2 CMT2Q DHTKD1 DHMN VB REEP1

12 Points to Consider: Inheritance Pattern How CMT is passed along in family Nerve Conduction Studies Slow in speed or reduced in strength Clinical History & Exam When did symptoms start and what they look like now

13 Genetic Testing Labs Many labs are now doing Next Generation Sequencing CMT testing: Athena Diagnostics 24 genes, >$10,000, 4 weeks GeneDx 54 genes, $4790, 6 weeks (when up and running, about 14 weeks now) InVitae 30 genes, $1500, 2-3 weeks Medical Neurogenetics 43 genes (+ mito testing, no PMP22 dup/del), $2300, 8 weeks Prevention Genetics dhmn panel, 17 genes, $2440, max 60 days

14 Narrowing genetic testing through NCVs, family history, and clinical exam can help lower test costs Working with a knowledgeable physician and genetic counselor to help Select possible genes Select Laboratory Medical insurance coverage How do I get genetic testing done in an affordable way?

15 In 2014, it is more likely to find the genetic cause if someone has CMT type 1 then CMT type 2 However, more genes that cause axonal neuropathy are being identified Still important to work with a physician and genetic counselor to help guide testing It is possible to participate in research to get free testing, but the trade off is time Is there DNA testing for CMT type 2? What do they look for?

16 YES!! New genetic causes of CMT have been found! 73 and counting New ways of performing genetic testing New laboratories doing testing Has genetic testing changed since 2004?

17 Chromosome Gene Gene ATCCAGCAGCAG GTG CTC AAG... Amino Acids Protein

18 Exome Sequencing

20 Exome Sequencing Sequence all genes that make a protein Will find many, many, many mutations Have to go through all mutations to find the one that causes symptoms Having at least 3 samples from a family can help to identify the gene

21 Example of Exome Results

22 How do I find out if a mutation I have is disease causing when it is reported as a variant of uncertain significance?

24 Do all members of a family who have CMT have the same type of CMT?

25 Family History: Modes of Inheritance Mike Shy Three main methods of inheritance: Autosomal Dominant Autosomal Recessive X-linked The method of inheritance does not change within a family

26 Autosomal Dominant Inheritance Affected Unaffected Unaffected Affected Unaffected Affected

27 Autosomal Dominant Inheritance

28 X-Linked Mom Dad Unaffected Female Unaffected Male Affected Female Affected Male

29 X-Linked Mom Dad Affected Female Unaffected Male Affected Female Unaffected Male

30 X-Linked Inheritance

31 Recessive Inheritance Unaffected Carrier Carrier Affected

32 Recessive Inheritance Carrier Carrier Carrier Carrier

33 Autosomal Recessive Inheritance

34 Is testing for CMT during pregnancy an option and how does one do this?

35 Family Planning Options During Pregnancy: Chorionic Villus Sampling (CVS) Amniocentesis Maternal fetal cell analysis Before Pregnancy: Preimplantation Genetic Diagnosis (PGD)

36 Prenatal Diagnosis

37 Preimplantation Genetic Diagnosis

INC-RDCRC http://rarediseasesnetwork.epi.usf.

38 INC-RDCRC Joins together 17 Sites from around the world doing research on CMT Collaboration of clinical data and samples to help further research Ultimately, improve patient care and treatment options

39 Your Questions?

Corporate Medical Policy

Corporate Medical Policy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: genetic_testing_for_diagnosis_of_inherited_peripheral_neuropathies 01/01/2019 N/A 01/01/2020 01/01/2019 Description