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

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.

Inclusion criteria

All patients must agree to take part in the study and sign a consent form. A teenager (age 13-17 years) considering enrolling must agree to take part in the study and sign an assent form (depending on local ethics committee requirements).

Additional inclusion criteria are described below.

Inclusion criteria

CMT1A Gene Modifier Study

Patients must have at least one of the following:

• Patient has a documented PMP22 duplication. AND/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.

Inclusion criteria

- Patients for CMT Exome Project

a. Patient has demonstrated neuropathy on nerve conduction studies or clinically diagnosed genetic neuropathy, in the opinion of the investigator or genetic counsellor.

Inclusion criteria

- Controls for CMT Exome Project

• Person is a family member of a CMT patient who is enrolled in the CMT Exome Project.

AND one of the following:

• Person does not have a peripheral neuropathy, in the opinion of the investigator or genetic counsellor.

OR

• Person is suspected to have a peripheral neuropathy, but has not been examined at an INC site.

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.).
• Patients with 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.