GDAP1-Related Charcot-Marie-Tooth Disease: Axonal or Demyelinating Subtype? Autosomal Recessive or Autosomal Dominant...

The GDAP1 gene encodes a mitochondrial outer membrane protein crucial for mitochondrial function. Mutations in this gene are associated with different subtypes of Charcot-Marie-Tooth (CMT) disease, inherited in either an autosomal recessive or dominant manner. In this study, we discuss the clinical and genetic aspects of 11 unrelated Iranian GDAP1-related CMT families.

The probands were selected from a large CMT cohort after whole exome sequencing (WES) analysis. 11 GDAP1-related CMT families-16 patients-were included in this study. Co-segregation analysis was performed to confirm the candidate variants.

In total, eight exonic variants in GDAP1 were identified; two were novel. Among all known variants, a deep intronic variant, c.311-23A>G, was found in two families. 11/16 patients were AR-CMT2K, three were CMT4A, and only two had AD-CMT2K.

Among our variants, two were more significant: c.311-23A>G, which has only been documented in another Iranian family and may represent a founder mutation within our population, and c.347T>G, which has exclusively been reported within the Italian population and is recognized as a founder mutation in that country. We found this variant in three unrelated families, suggesting that this variant is not confined to Italy and that codon 347 may be a hotspot codon. Our findings extend the clinical and genetic aspects of GDAP1-related CMT and emphasize the need to consider intronic variants in genetic analysis. Additionally, we highlight that AD-CMT2K has a milder phenotype than other GDAP1-related disease types, which could result in an underestimation of the number of AD-CMT2K cases.