Novel Dominant Splicing Variant in MPZ Associated With Unusual Charcot–Marie–Tooth Disease

Background and Aims Variants in the myelin protein zero coding MPZ gene are responsible for a broad spectrum of peripheral demyelinating and axonal neuropathies, including different types of Charcot–Marie–Tooth diseases, challenging for genotype–phenotype correlation. Methods Minigene splicing reporter assay was used to unveil the pathogenic mechanism of a novel MPZ (NM_000530.8) c.234 + 1G>C p.(?) heterozygous splice variant. Results The variant was identified in a 47‐year‐old female patient presenting with atypical clinical features, including balance disturbance with positive Romberg, absent Achilles tendon reflexes, distal hypoesthesia and bulbar involvement, including dysarthria and dysphagia. Electromyography revealed a sensory‐motor neuropathy with moderately reduced nerve conduction velocities. In silico analysis predicted this variant to disrupt the consensual donor splice site located in intron 2 of MPZ . Minigene construction confirmed the functional impact of this variant, revealing exon 2 skipping and the apparition of a premature termination codon. Interpretation This case expends the genotype–phenotype correlations of MPZ ‐related Charcot–Marie–Tooth diseases, associating atypical mild phenotype with a rare splice dominant variant, and provides new insights into MPZ haploinsufficiency and pathogenic mechanisms.