A 78-Kilobase (kb) interchromosomal DNA insertion within the CMTX3 locus appears to be a cause of Charcot-Marie-Tooth Neuropathy

This topic is not directly associated with “gene-environment interactions”, … but rather shows what COOL THINGS can be discovered about Mendelian diseases by performing next-generation sequencing (NGS) or whole-genome sequencing (WGS) technology to understand serious clinical congenitcal syndromes––in this case, Charcot-Marie-Tooth (CMT) disease. CMT is an X-linked dominant inherited peripheral neuropathy and peroneal muscular atrophy (muscles below the knee and inserting into the foot) is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, affecting approximately 1 in 2,500 people. This disease is seen more often in family inbreeding (marriage of cousins, etc.).

The cause of CMT remains unsolved in many patients––even after all protein-coding sequences have been interrogated by way of whole-exome sequencing (WES) studies. The pathogenic mutations in these unsolved families may reflect: non-coding point mutations, small insertions/deletions (indels), or large structural variations involving thousands to millions of base pairs in or near the CMTX3 gene. In two large, distantly related families with X-linked CMT, authors [see attached paper] tested for all known protein-coding sequence variants, and no causal variant was found.

Using WGS, authors identified a 78-kb segment of chromosome 8q24.3 inserted into chromosome Xq27.1 as the likely underlying cause of neuropathy in these two families.

This is the first report of a large insertion causing CMT. This study highlights an understudied disease mechanism for inherited peripheral neuropathy.


PLoS Genet 2o16; 12: e1006177

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.