Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

Area of Science:

• Neurogenetics
• Molecular Biology
• Clinical Neurology

Background:

• Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are typically linked to autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy.
• Rarely, GDAP1 mutations present as autosomal dominant Charcot-Marie-Tooth (ADCMT), suggesting a broader genetic and phenotypic spectrum.

Purpose of the Study:

• To determine the frequency of pathogenic heterozygous GDAP1 mutations in ADCMT.
• To characterize the clinical and electrophysiologic phenotype associated with dominant GDAP1 mutations.

Main Methods:

• Mutation analysis of GDAP1 coding regions and exon-intron boundaries in a large ADCMT cohort.
• Exclusion of intragenic GDAP1 deletions using allele quantification.
• In vitro functional assays to confirm pathogenicity of a novel variant by assessing mitochondrial function.

Main Results:

• Identified 4 pathogenic heterozygous GDAP1 mutations (3 novel) in 8 CMT families.
• Observed reduced disease penetrance in three of the identified mutations.
• Phenotype variability included variable onset (childhood to adulthood), slow progression, milder severity than ARCMT, and predominantly axonal neuropathy.

Conclusions:

• Broadened the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies.
• Demonstrated that dominant GDAP1 mutations can cause axonal CMT with variable clinical and electrophysiologic findings.
• Validated cell-based functional assays for pathogenic variant assessment and discussed implications for CMT diagnostics and counseling.