Journal
NEUROMUSCULAR DISORDERS
Volume 25, Issue 10, Pages 794-799Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2015.07.017
Keywords
IGHMBP2; Next-generation sequencing; Charcot-Marie Tooth disease; Hereditary sensory and motor neuropathy; Spinal muscular atrophy with respiratory distress 1
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Funding
- Genome Canada
- Ontario Genomics Institute
- Genome Quebec
- Reseau de Medecine Genique appliquee
- CIHR Institute of Genetics Clinical Investigatorship Award
- Canadian Institutes of Health Research
- Ontario Research Fund
- Children's Hospital of Eastern Ontario Foundation
- Fonds de la recherche en sante du Quebec
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Charcot-Marie-Tooth disease is a group of genetically heterogeneous disorders characterized by a sensorimotor polyneuropathy with subsequent muscle atrophy, areflexia, and sensory loss. More than 60 genes have been linked to Charcot-Marie-Tooth phenotypes, including IGHMBP2. Until recently, mutations in IGHMBP2 were exclusively associated with spinal muscular atrophy with respiratory distress (SMARD1). We present a sibling pair with a novel homozygous truncating mutation in IGHMBP2. The patients presented with childhood-onset distal weakness, wasting in the upper and lower limbs, areflexia and decreased sensation, but no respiratory involvement. Exome sequencing was performed and a homozygous variant was identified (c.2601_2604del; p.Lys868Profs*109). Sanger sequencing confirmed the presence of this variant in a homozygous state in the two affected siblings, while both parents were heterozygous. Further analyses showed decreased mRNA and IGHMBP2 protein in a lymphoblast cell line derived from one of the siblings. We demonstrate the utility of next-generation sequencing in reaching a molecular diagnosis for a heterogeneous condition such as Charcot-Marie-Tooth. Taken together, our data and that from the literature suggest that the spectrum of clinical presentations associated with mutations in IGHMBP2 may be secondary, at least in part, to the amount of residual protein. (C) 2015 Elsevier B.V. All rights reserved.
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