Identifying genetic factors that cause and modify CMT (Project 2)

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Abstract Genetics is at the core of CMT diagnoses, pathophysiology, and preparation for trials and gene therapy approaches. The latter requires precise genetic diagnosis for each individual patient and genetics will also be highly informative for long-term outcomes. However, even with 90+ CMT and related genes identified, over 50% of CMT2 patients do not receive a diagnosis today. This gap in heritability has many potential explanations, including additional CMT genes to be discovered, non-coding mutations, unconventional variation (i.e. repeat expansions), oligogenic inheritance, and Variants of Unknown Significance. Our long-term commitment to the genetic modifier study in CMT1A has yielded a genome wide significant association (GWAS) of SIPA1L2 as the first CMT1A modifier gene. Importantly, this discovery promises a novel strategy to correct the increased gene dosage of PMP22. The INC has collected 1,700 samples of CMT1A patients and another 1,000 are expected over the next five years. With new statistical methods and genome sequencing now available we will bring this unparalleled effort to its full potential by combining all these strengths and comprehensively define the genetic architecture of CMT1A. We anticipate that some of these risk factors have effects on other more common types of CMT, such as CMT1B, CMTX, and CMT2A. Over the past funding period, we have discovered 22+ novel CMT and related genes, including a CMT causing repeat expansion disease. We will continue this work, but focus on improving our sample and data resources in size and ancestral diversity. This will be achieved by further expanding data sharing with CMT-ID, AOINC, and the MRC in the UK. We will develop a CMT genetic data archive and utilize the GENESIS genomic software platform that has helped to discover most of the above mentioned CMT genes. Finally, in the previous funding cycle we have created the Inherited Neuropathy Variant Browser (INVB) to collect disease related variation in CMT genes internationally and provide this information openly to the community. Given our specialized interest in CMT and related disorders and our international reach, this CMT-focused effort goes far beyond the reach of NIH ClinVar. We will develop INVB version 2.0 that includes more data, additional correlations, and deeper information on VUS. Specifically, we propose to (1) Perform an Iterative expansion of modifier studies in CMT1A and other relatively common CMT subtypes, (2) Build a sustained infrastructure for data sharing and continued discovery of new CMT genes, and (3) Develop the CMT variant browser 2.0 that will also provide a phenotype bank for CMT enabling patients and investigators to rapidly obtain diagnostic and de-identified clinical information on disease causing mutations.