Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A, New Causes of CMT2

Study Overview
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Brief Summary
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This project includes two projects. One is looking for new genes that cause Charcot Marie Tooth disease (CMT). The other is looking for genes that do not cause CMT, but may modify the symptoms a person has.

Detailed Description
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This project is to understand modifier genes and how they influence the severity of disease expression, along with identifying new forms of CMT which have not been genetically determined. Subjects who are eligible will either have CMT type 1A (CMT1A) or an unknown form of CMT. Blood will be drawn and sent to the University of Miami where they receive the coded sample and process it through exome sequencing. Subjects will be told that this is optional.

Official Title
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Genetics of Charcot Marie Tooth Disease (CMT) - Modifiers of CMT1A, New Causes of CMT

Conditions
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HMSN, Charcot-Marie-Tooth Disease, Type Ia (Disorder)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient MUST be seen in person at one of the clinical sites involved in this study. Charcot Marie Tooth disease type 1A (CMT1A) modifier gene study Patient has a documented PMP22 duplication OR Patient has a first or second degree relative (parent, child, sibling, half-sibling, aunt, uncle, grandparent, grandchild, niece, or nephew) with a documented PMP22 duplication AND a clear link between that family member and the affected patient AND a phenotype consistent with CMT1A. i. A clear link is necessary for a second-degree relative. For example, if a grandparent is affected and has a PMP22 duplication, and the parent does not have any signs, symptoms, or electrophysiology consistent with CMT1A, there is no clear link. ii. In cases where clear links are not available, genetic testing is required for the patient or the first degree family member who is not clearly affected. AND Patient has agreed to take part in the study and has signed a consent form. A teenager (ages 13-17) considering enrolling must agree to take part in the study and sign an assent form Inclusion Criteria - CMT Exome Project Patient has demonstrated neuropathy on nerve conduction studies or a clinically diagnosed genetic neuropathy. Patient or first or second degree family member with a clear link as described in the CMT1A Inclusion Criteria part b has had negative MFN2 genetic testing, if has an axonal form of CMT (nerve conductions greater than 38 m/s) or negative testing for PMP22 duplication, deletion, sequencing, MPZ, and GJB1 if a demyelinating form of CMT is present (<38 m/s). More than one family member is willing eligible to participate. i. Sample pedigrees showing optimal degrees of relationship are shown below. ii. Participation includes being able to complete all aspects of the study, including the giving informed consent, having a brief physical examination, and providing a DNA sample. d. Patient has agreed to take part in the study and has signed a consent form. e. A teenager (ages 13-17) considering enrolling must agree to take part in the study and sign an assent form. Inclusion Criteria - Controls Person does not have a peripheral neuropathy, as determined by the investigator. Person has understood the study and signed an IRB approved consent form. Teenagers (age 13-17 years) must sign an assent form. Exclusion Criteria: Patient does not wish to participate or does not sign a consent form. For CMT Exome Project, patient has a genetically confirmed form of CMT (i.e. mutation in MFN2 causing CMT2A, mutation in GARS causing CMT2D, etc.). Known neuropathy from a non-genetic source, such as chemotherapies (i.e. Vincristine, Taxol, Cisplatin), diabetes, alcoholism will be evaluated independently so that genetic contributions to their effects on CMT1A phenotypes can also be analyzed.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CMT1A<br>Families/people with genetically defined CMT1A | |
| Genetically undefined CMT<br>Families/people with genetically undefined CMT with common causes ruled out. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Charcot Marie Tooth disease type 1A (CMT1A) gene modifiers | While the same genetic change - an extra copy of PMP22 - causes CMT1A by definition, it is unclear why some people have more severe symptoms and some have less severe. We are looking for genetic modifiers - changes in the DNA that may be causing the differences in symptoms. | once | 
| New genetic causes of CMT | At least 33% of people with CMT have an unknown or genetically un-found form of the condition. We are looking for additional genes that cause CMT when mutated. | Once | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMT, CMT1A