Özet:
Inherited peripheral neuropathies are a group of genetic disorders of the periph eral nervous system. The most common type is called Charcot-Marie-Tooth (CMT) disease that constitutes an interesting research focus due to its clinical and genetic heterogeneity. Mutations in more than 90 genes and loci are associated with CMT that presents with autosomal dominant (AD), autosomal recessive (AR), X-linked, or mitochondrial inheritance. Despite the advances in genetic testing, approximately 35% of all CMT cases worldwide remain without a molecular diagnosis. The diagnostic rate is even lower for ARCMT due to the presence of many individually rare genes. This diagnostic gap points to the presence of yet unidentified causative genes, as well as po tential non-Mendelian features of the disease. In order to identify novel genes/alleles causing ARCMT and determine the frequency for known genes in Turkey, we have analyzed 56 consanguineous families diagnosed with CMT who present with early on set polyneuropathy with additional symptoms. Through the screening of patients for GDAP1 mutations, and subsequent whole-exome sequencing and homozygosity map ping, we have identified 22 recurrent and 13 novel alleles in known CMT genes achieving a potential diagnosis rate of 62,5%. Moreover, we identified FXN as a candidate gene for a novel disease in the spectrum between CMT and Friedreich’s ataxia, ATP8B3 for ARCMT2, and SEPT11 for AR-cerebellar ataxia with axonal neuropathy. This study paints the genetic landscape of the Turkish ARCMT population, reports candidate genes that might enlighten new disease mechanisms, and can serve as a reference for diagnosis strategies specific to populations with similar genetic backgrounds.
