Abstract
Charcot-Marie-Tooth disease (CMT) refers to a group of clinically and genetically heterogeneous inherited neuropathies. Ganglioside-induced differentiation-associated protein 1 GDAP1-related CMT has been reported in an autosomal dominant or recessive form in patients presenting either axonal or demyelinating neuropathy. We report two Sri Lankan sisters born to consanguineous parents and presenting with a severe axonal sensorimotor neuropathy. The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT. However, sequencing of the coding regions of the gene was normal. Whole-exome sequencing (WES) was performed and revealed that the largest region of homozygosity was around GDAP1 with several variants, mostly in non-coding regions. In view of the high clinical suspicion of GDAP1 gene involvement, we examined the variants in this gene and this, along with functional studies, allowed us to identify an alternative splicing site revealing a cryptic in-frame stop codon in intron 4 responsible for a severe loss of wild-type GDAP1. This work is the first to describe a deleterious mutation in GDAP1 gene outside of coding sequences or intronic junctions and emphasizes the importance of interpreting molecular analysis, and in particular WES results, in light of the clinical and electrophysiological phenotype.
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Abbreviations
- CMT :
-
Charcot-Marie-Tooth disease
- AR-CMT :
-
autosomal recessive CMT
- GDAP1 :
-
ganglioside-induced differentiation-associated protein 1
- WES :
-
whole-exome sequencing
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JP is funded by Association pour le Développement de la Neurogénétique (Hospices Civils de Lyon DRCI 69HCL15_0734).
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MM, TS, and PL were involved in the conception and design of the research project, analysis and interpretation of the data, and writing of the first draft of the manuscript. TS was involved in the acquisition of clinical data, and PL, JP, and GPL were involved in the acquisition of molecular data. All authors read and approved the final manuscript. RYC was involved in the acquisition and interpretation of whole-body MRI.
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Masingue, M., Perrot, J., Carlier, RY. et al. WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon. Neurogenetics 19, 67–76 (2018). https://doi.org/10.1007/s10048-018-0539-7
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DOI: https://doi.org/10.1007/s10048-018-0539-7